Common Alterations Research Articles

Common alterations in plasma free amino acid profiles and gut microbiota-derived tryptophan metabolites of five types of cancer patients.

Amino acids not only play a vital role in the synthesis of biological molecules such as proteins in cancer malignant cells, they are also essential metabolites for immune cell activation and antitumor effects in the tumor microenvironment. The abnormal changes in amino acid metabolism are closely related to the occurrence and development of tumors and immunity. Intestinal microorganisms play an essential role in amino acid metabolism, and tryptophan and its intestinal microbial metabolites are typical representatives. However, it is known that the cyclic amino acid profile is affected by specific cancer types, so relevant studies mainly focus on one type of cancer and rarely study different cancer forms at the same time. The objective of this study was to examine the PFAA profile of five cancer patients and the characteristics of tryptophan intestinal microbial metabolites to determine whether there are general amino acid changes across tumors. Plasma samples were collected from esophageal (n = 53), lung (n = 73), colorectal (n = 94), gastric (n = 55), breast cancer (n = 25), and healthy control (HC) (n = 139) subjects. PFAA profile and tryptophan metabolites were measured, and their perioperative changes were examined using high-performance liquid chromatography. Univariate analysis revealed significant differences between cancer patients and HC. Furthermore, multivariate analysis discriminated cancer patients from HC. Regression diagnosis models were established for each cancer group using differential amino acids from univariate analysis. Receiver-operating characteristic analysis was applied to evaluate these diagnosis models. Finally, GABA, arginine, tryptophan, taurine, glutamic acid, and melatonin showed common alterations across all types of cancer patients. Metabolic pathway analysis shows that the most significant enrichment pathways were tryptophan, arginine, and proline metabolism. This study provides evidence that common alterations of the metabolites mentioned above suggest their role in the pathogenesis of each cancer patient. It was suggested that multivariate models based on PFAA profiles and tryptophan metabolites might be applicable in the screening of cancer patients.

Formation of giant iron oxide-copper-gold deposits by superimposed episodic hydrothermal pulses

Iron oxide-copper-gold (IOCG) deposits are a globally important source of copper, gold and critical commodities. Despite their relevance, IOCG deposits remain an ill-defined clan, with a range of characteristics that has complicated development of the general genetic model. Here we focus on the Candelaria IOCG deposit in Chile and reveal that by using micro-textural and compositional variations in actinolite, a common alteration mineral found in many IOCG deposits, we can constrain the evolution of these systems. We demonstrate that Candelaria formed by the superposition of at least two pulses of mineralization with a late Cu-rich event overprinting and superimposed over an early, and probably higher temperature, iron oxide-apatite (IOA) mineralization event. These distinct pulses were likely caused by episodic injections of magmatic-hydrothermal fluids from crystallizing magmas at depth. Our data provide empirical evidence of grain-to-deposit scale compositional and potentially temperature changes in an IOCG system. The results support the use of actinolite chemistry as a novel approach to understand the formation of IOCG deposits and a potential tool for vectoring in exploration.

Distinct impact of arbuscular mycorrhizal isolates on tomato plant tolerance to drought combined with chronic and acute heat stress

Arbuscular mycorrhizal (AM) fungi could mitigate individual drought and heat stress in host plants. However, there are still major gaps in our understanding of AM symbiosis response to the combined stresses. Here, we compared seven AM fungi, Rhizophagus irregularis, Funneliformis mosseae, Funneliformis geosporum, Funneliformis verruculosum, Funneliformis coronatum, Septoglomus deserticola, Septoglomus constrictum, distributed to many world regions in terms of their impacts on tomato endurance to combined drought and chronic heat as well as combined drought and heat shock. A multidisciplinary approach including morphometric, ecophysiological, biochemical, targeted metabolic (by ultrahigh-performance LC-MS), and molecular analyses was applied. The variation among AM fungi isolates in the enhancement in leaf water potential, stomatal conductance, photosynthetic activity, and maximal PSII photochemical efficiency, proline accumulation, antioxidant enzymes (POD, SOD, CAT), and lowered ROS markers (H2O2, MDA) in host plants under combined stresses were observed. S. constrictum inoculation could better enhanced the host plant physiology and biochemical parameters, while F. geosporum colonization less positively influenced the host plants than other treatments under both combined stresses. F. mosseae- and S. constrictum-associated plants showed the common AM-induced modifications and AM species-specific alterations in phytohormones (ABA, SA, JA, IAA), aquaporin (SlSIP1-2; SlTIP2-3; SlNIP2-1; SlPIP2-1) and abiotic stress-responsive genes (SlAREB1, SlLEA, SlHSP70, SlHSP90) in host plants under combined stresses. Altogether, mycorrhizal mitigation of the negative impacts of drought + prolonged heat and drought + acute heat, with the variation among different AM fungi isolates, depending on the specific combined stress and stress duration.

BET inhibitors induce NF-κB and E2F downregulation in Hodgkin and Reed–Sternberg cells

The prognosis of patients with relapsed and/or refractory classic Hodgkin lymphoma (cHL) continues to be poor. Therefore, there is a continuing need to develop novel therapies and to rationalize the use of target combinations. In recent years there has been growing interest in epigenetic targets for hematological malignancies under the rationale of the presence of common alterations in epigenetic transcriptional regulation. Since Hodgkin and Reed–Sternberg (HRS) cells have frequent inactivating mutations of the CREBBP and EP300 acetyltransferases, bromodomain and extra-terminal (BET) inhibitors can be a rational therapy for cHL. Here we aimed to confirm the efficacy of BET inhibitors (iBETs) using representative cell models and functional experiments, and to further explore biological mechanisms under iBET treatment using whole-transcriptome analyses. Our results reveal cytostatic rather than cytotoxic activity through the induction of G1/S and G2/M cell-cycle arrest, in addition to variable MYC downregulation. Additionally, massive changes in the transcriptome induced by the treatment include downregulation of relevant pathways in cHL disease: NF-kB and E2F, among others. Our findings support the therapeutic use of iBETs in selected cHL patients and reveal previously unknown biological mechanisms and consequences of pan-BET inhibition.

Aura phenomena do not initiate migraine attacks-Findings from neuroimaging.

As cortical spreading depolarization (CSD) has been suggested to be the cause of migraine aura and as CSD can activate trigeminal nociceptive neurons in animals, it has been suggested that CSD may be the cause of migraine attacks. This raises the question of how migraine pain is generated in migraine attacks without aura and has led to the hypothesis that CSD may also occur in subcortical regions in the form of "silent" CSDs, and accordingly "silent auras". In this case study, we provide evidence for common neuronal alterations preceding headache attacks with and without aura in a male patient with migraine, who underwent daily event-correlated functional magnetic resonance imaging of trigeminal nociception for a period of 30 days. During these days the man experienced migraine attacks with and without aura. Comparing the preictal phases between both attack types revealed a common hyperactivation of the hypothalamus (p < 0.01), which was already present 2 days before the actual attack. The time frame of the central pathophysiological orchestration of migraine attacks, irrelevant of the presence of later aura, strongly suggests that the aura is an epiphenomenon that is unrelated and does not initiate headache attacks.

THE CLINICAL AND MOLECULAR LANDSCAPE OF GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS

Abstract Molecular alterations in gliomas in adolescents and young adults (AYA) have not been comprehensively described to date. To determine the impact of mutation, we performed a population based study of gliomas in AYA. METHODS: Patients diagnosed from 2000-2019 with glioma between 15-39.9 years were eligible. Comprehensive molecular analysis was performed. Therapeutic and outcome data was collected. For comparison, analysis included patients aged 0-39.9 years. RESULTS: A total of 876 AYA gliomas were included. Genetic alterations were found in 95% of available tumours. Pediatric-type mutations were found in 33% of AYA tumours. The most common paediatric alterations included BRAF p.V600E (11%) and FGFR alterations (7%) while BRAF fusions (4%), H3 p.K27M (4%) and H3.3 p.G34R (1%) were rare. IDH mutation was found in 57% of tumours. Molecular GBM accounted for 7%. Paediatric-type alterations had different outcomes in AYA than children. Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma (LGG), compared to 14% and 25% for BRAF- V600E and FGFR-altered high grade glioma (HGG) respectively. BRAF and FGFR mutant tumours had higher proportion of HGG versus LGG in AYA compared to children (OR 2.6, 95% CI 1.2-5.6) while outcome was improved in LGG in AYA compared to children with a 10 year PFS of 76.8% vs 51.6% respectively (p=0.0009) suggesting a transition phase occurring during adolescence and early adulthood. CONCLUSIONS: AYA gliomas are enriched for paediatric-type alterations with distinct outcomes. Routine analysis is required given the role for targeted inhibitors.

MRI characteristics predict BRAF V600E status in gangliogliomas and pleomorphic xanthoastrocytomas and provide survival prognostication.

BRAF V600E mutation is a common genomic alteration in gangliogliomas (GGs) and pleomorphic xanthoastrocytomas (PXAs) with prognostic and therapeutic implications. To investigate the ability of magnetic resonance imaging (MRI) features to predict BRAF V600E status in GGs and PXAs and their prognostic values. A cohort of 44 patients with histologically confirmed GGs and PXAs was reviewed retrospectively. BRAF V600E status was determined by immunohistochemistry (IHC) staining and fluorescence quantitative polymerase chain reaction (PCR). Demographics and MRI characteristics of the two groups were evaluated and compared. Univariate and multivariate Cox regression analyses were performed to identify MRI features that were prognostic for progression-free survival (PFS). T1/FLAIR ratio, enhancing margin, and mean relative apparent diffusion coefficient (rADCmea) value showed significant differences between the BRAF V600E-mutant and BRAF V600E-wild groups (all P < 0.05). Binary logistic regression analysis revealed only rADCmea value was the independent predictive factor for BRAF V600E status (P = 0.027). Univariate Cox regression analysis showed age at diagnosis (P = 0.032), WHO grade (P = 0.020), enhancing margin (P = 0.029), and rADCmea value (P = 0.005) were significant prognostic factors for PFS. In multivariate Cox regression analysis, increasing age (P = 0.040, hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 1.002-1.079) and lower rADCmea values (P = 0.021, HR = 0.036, 95% CI = 0.002-0.602) were associated with poor PFS in GGs and PXAs. Imaging features are potentially predictive of BRAF V600E status in GGs and PXAs. Furthermore, rADCmea value is a valuable prognostic factor for patients with GGs or PXAs.

CCNB1IP1 prevents ubiquitination-mediated destabilization of MYCN and potentiates tumourigenesis of MYCN-amplificated neuroblastoma.

MYCN amplification as a common genetic alteration that correlates with a poor prognosis for neuroblastoma (NB) patients. However, given the challenge of directly targeting MYCN, indirect strategies to modulate MYCN by interfering with its cofactors are attractive in NB treatment. Although cyclin B1 interacting protein 1 (CCNB1IP1) has been found to be upregulated in MYCN-driven mouse NB tissues, its regulation with MYCN and collaboration in driving the biological behaviour of NB remains unknown. To evaluate the expression and clinical significance of CCNB1IP1 in NB patients, public datasets, clinical NB samples and cell lines were explored. MTT, EdU incorporation, colony and tumour sphere formation assays, and a mouse xenograft tumour model were utilized to examine the biological function of CCNB1IP1. The reciprocal manipulation of CCNB1IP1 and MYCN and the underlying mechanisms involved were investigated by gain- and loss-of-function approaches, dual-luciferase assay, chromatin immunoprecipitation (CHIP) and co-immunoprecipitation (Co-IP) experiments. CCNB1IP1 was upregulated in MYCN-amplified (MYCN-AM) NB cell lines and patients-derived tumour tissues, which was associated with poor prognosis. Phenotypic studies revealed that CCNB1IP1 facilitated the proliferation and tumourigenicity of NB cells in cooperation with MYCN in vitro and in vivo. Mechanistically, MYCN directly mediates the transcription of CCNB1IP1, which in turn attenuated the ubiquitination and degradation of MYCN protein, thus enhancing CCNB1IP1-MYCN cooperativity. Moreover, CCNB1IP1 competed with F box/WD-40 domain protein 7 (FBXW7) for MYCN binding and enabled MYCN-mediated tumourigenesis in a C-terminal domain-dependent manner. Our study revealed a previously uncharacterized mechanism of CCNB1IP1-mediated MYCN protein stability and will provide new prospects for precise treatment of MYCN-AM NB based on MYCN-CCNB1IP1 interaction.

ASSOCIATION BETWEEN SLEEP QUALITY AND GERIATRIC SYNDROMES IN NURSING HOME RESIDENTS

Background: With aging, an increase is observed in some geriatric syndromes as well as sleep disorders. Objective: The aim of this study is to investigate the relationship between sleep quality and geriatric syndromes (dementia, depression, sarcopenia, malnutrition, and frailty) in nursing home residents. Methods: The participants’ demographic characteristics, comorbid diseases, number of drugs, cognitive performance, mood and nutritional states, sarcopenia and fraility screening tests and sleep quality test were evaluated by two geriatricians. The participants were divided into two groups as good sleep quality and poor sleep quality. Correlation analysis of sleep quality and geriatric and mental functionality tests was performed with Spearman correlation analysis. Results: A total of 104 nursing home residents (34 females, 74 males, aged 61-98) participated in the study. Sleep quality was found to be worse in the elderly between the ages of 75-84, with a higher number of children, using assistive devices, and taking selective serotonin reuptake inhibitors. In addition, in participants with poor sleep quality, SARC-f (strength, assistance with walking, rising from a chair, climbing stairs, and falls) and geriatric depression scale scores were significantly higher. The Pittsburgh Sleep Quality Index global score was negatively associated with total sleep time and positively associated with geriatric depression scale score and SARC-f score. Conclusion: Findings from the present study in relation between poor sleep quality and some geriatric evaluation parameters suggests that there may be a common pathophysiological alteration with aging.

Genetic characteristics of advanced oral tongue squamous cell carcinoma in young patients

ObjectivesWe aimed to investigate genetic alterations in oral tongue squamous cell carcinoma (OTSCC) based on age and the clinical significance of these alterations in young OTSCC patients. Materials and MethodsWe detected genetic alterations in 44 cases of advanced OTSCC through next-generation sequencing and analyzed and compared patients either younger or older than 45 years. Further analysis was conducted on a validation group of 96 OTSCC patients aged ≤ 45 years to examine the clinical and prognostic associations of TERT promoter (TERTp) mutations. ResultsTP53 mutation was the most common genetic alteration in advanced OTSCC (88.6%), followed by TERTp mutation (59.1%), CDKN2A mutation (31.8%), FAT1 mutation (9.1%), NOTCH1 mutation (9.1%), EGFR amplification (18.2%), and CDKN2A homozygous deletion (4.5%). TERTp mutation was the only genetic alteration significantly enriched in young patients (81.3% in young versus 46.4% in older; P < 0.024). Within the validation group of young patients, TERTp mutation was identified in 30 cases (30/96, 31.3%) and tended to be related to both smoking and alcohol consumption (P = 0.072), higher stage (P = 0.002), more frequent perineural invasion (P = 0.094), and worse overall survival (P = 0.012) than wild type. ConclusionOur findings suggest that TERTp mutation is more frequent in young patients with advanced OTSCC and is associated with worse clinical outcomes. Therefore, TERTp mutation may serve as a prognostic biomarker for OTSCC in young patients. The findings of this study may help in developing personalized treatment strategies for OTSCC based on age and genetic alterations.

The Challenges and Opportunities of the Implementation of Comprehensive Genomic Profiling in Everyday Clinical Practice with Non-Small Cell Lung Cancer: National Results from Croatia

Non–small cell lung cancer (NSCLC) has become the best example of precision oncology’s impact on outcomes in everyday clinical practice, significantly changing the expectations of all stakeholders, including medical professionals, society, and most importantly, patients. Consequently, the implementation of the precision oncology concept in medical systems, in order to achieve optimal and proven curative effects in NSCLC, is imperative. In this study, we investigated the development, challenges, and results associated with the implementation of precision oncology in NSCLC on a national level in Croatia. We conducted a multicenter, retrospective, cross-sectional analysis on the total population of Croatian patients with metastatic lung cancer, on whose tumors specimen comprehensive genomic profiling (CGP) testing was performed during 2020 and 2021. A total of 48 patients were included in the study. CGP revealed clinically relevant genomic alterations (CRGA) in 37 patients (79%), with a median of 2 (IQR 1–3) CRGA per patient. From the panel of recommended tests, KRAS, MET, and EGFR were the most common alterations, detected in 16 (34%), 5 (11%), and 3 (6%) patients, respectively. CGP revealed additional targetable mutations in 29 (60%) patients who would not have been tested (and consequently, whose mutations would not have been detected) according to the existing everyday standard of practice in Croatia. The tumor mutational burden was reported as high (≥10 Muts/Mb) in 19 patients (40%). CGP analysis reported some kind of targeted therapy for 34 patients (72%). CGP revealed other potentially targetable mutations, and it also determined TMB to be high in a significant number of patients. In conclusion, when possible, CGP should be used as an upfront backbone diagnostic and treatment-oriented work-up in patients with NSCLC.

T2-FLAIR Mismatch Sign in Pediatric Low-Grade Glioma.

No qualitative imaging feature currently predicts molecular alterations of pediatric low-grade gliomas with high sensitivity or specificity. The T2-FLAIR mismatch sign predicts IDH-mutated 1p19q noncodeleted adult gliomas with high specificity. We aimed to assess the significance of the T2-FLAIR mismatch sign in pediatric low-grade gliomas. Pretreatment MR images acquired between January 2001 and August 2018 in pediatric patients with pediatric low-grade gliomas were retrospectively identified. Inclusion criteria were the following: 1) 0-18 years of age, 2) availability of molecular information in histopathologically confirmed cases, and 3) availability of preoperative brain MR imaging with non-motion-degraded T2-weighted and FLAIR sequences. Spinal cord tumors were excluded. Three hundred forty-nine patients were included (187 boys; mean age, 8.7 [SD, 4.8] years; range, 0.5-17.7 years). KIAA1549-B-Raf proto-oncogene (BRAF) fusion and BRAF p.V600E mutation were the most common molecular markers (n = 148, 42%, and n = 73, 20.7%, respectively). The T2-FLAIR mismatch sign was present in 25 patients (7.2%). Of these, 9 were dysembryoplastic neuroepithelial tumors; 8, low-grade astrocytomas; 5, diffuse astrocytomas; 1, a pilocytic astrocytoma; 1, a glioneuronal tumor; and 1, an angiocentric glioma. None of the 25 T2-FLAIR mismatch pediatric low-grade gliomas were BRAF p.V600E-mutated. Fourteen of 25 pediatric low-grade gliomas with the T2-FLAIR mismatch sign had rare molecular alterations, while the molecular subtype was unknown for 11 tumors. The T2-FLAIR mismatch sign was not observed in the common molecular alterations, BRAF p.V600E-mutated and KIAA1549-BRAF fused pediatric low-grade gliomas, while it was encountered in pediatric low-grade gliomas with rare pediatric molecular alterations.

Zooplankton in the Technogenic Aquatic Ecosystem of the North Crimean Canal, the Longest in Europe

The construction and use of navigation and irrigation canals are among the common human alterations in landscapes and ecosystems. The North Crimean Canal (NCC) is the longest in Europe; its main branch is 403 km, and the total of all its branches exceeds 10,000 km. It is a main driver of the significant environmental changes in an all-arid part of Crimea. No zooplankton studies in the canal have been carried out up to this time at all. In 2022, zooplankton was studied in different sites from May to October. Total zooplankton abundance fluctuated between 170 and 19,560 ind. m−3, and wet biomass between 0.75 and 1057 mg m−3. In total, 11 Rotifera species, 11 Cladocera species, and 15 Copepoda species, including 2 Harpacticoida, 5 Calanoida, and 8 Cyclopoida, were found in plankton. The most common Rotifera species were Brachionus calyciflorus, Euchlanis dilatate, and Keratella cochlearis. Among Cladocera, Chydorus sphaericus, Bosmina longirostris, and Coronatella rectangular have the highest frequency of occurrence. In Copepoda, these were Acanthocyclops vernalis, Eurytemora affinis, and Nitocra typica. Among the 37 species found in NCC, 10 were not previously noted in the water bodies of Crimea. Among rotifers, they were Ploesoma hudsoni, Polyarthra dolichoptera, Pompholyx complanata, Synchaeta grandis, and Synchaeta stylata. Bosminopsis zernowi, Rhynchotalona rostrata, and Scapholeberis mucronata were not noted before among Cladocera. Eurytemora lacustris and Cyclops smirnovi were first found in Crimea among Copepoda. New technogenic aquatic ecosystems such as NCC are the “gateway” for the invasion of alien species into the new regions.

Clinical and Genomic Characterization of Pancreatic Ductal Adenocarcinoma with Signet-Ring/Poorly Cohesive Cells

Signet-ring cell (SRC)/poorly cohesive cell carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its clinicopathologic and molecular profiles based on a multi-institutional cohort of 20 cases.The molecular profiles were investigated using DNA and RNA sequencing. The clinicopathologic parameters and molecular alterations were analyzed based on survival indices and using a validation/comparative cohort of 480 conventional PDAC patients.The primary findings were as follows: (1) clinicopathologic features: SRC carcinomas are highly aggressive neoplasms with poor prognosis, and the lungs are elective metastatic sites; (2) survival analysis: a higher SRC component was indicative of poorer prognosis. In particular, the most clinically significant threshold of SRC was 80%, showing statistically significant differences in both disease-specific and disease-free survival; (3) genomic profiles: SRC carcinomas are similar to conventional PDAC with the most common alterations affecting the classic PDAC drivers KRAS (70% of cases), TP53 (55%), SMAD4 (25%), and CDKN2A (20%). EGFR alterations, RET::CCDC6 fusion gene, and microsatellite instability (3 different cases, 1 alteration per case) represent novel targets for precision oncology. The occurrence of SMAD4 mutations was associated with poorer prognosis; (4) pancreatic SRC carcinomas are genetically different from gastric SRC carcinomas: CDH1, the classic driver gene of gastric SRC carcinoma, is not altered in pancreatic SRC carcinoma; (5) transcriptome analysis: the cases clustered into 2 groups, one classical/exocrine-like, and the other squamous-like; and (6) SRC carcinoma-derived organoids can be successfully generated, and their cultures preserve the histologic and molecular features of parental SRC carcinoma.Although pancreatic SRC carcinoma shares similarities with conventional PDAC regarding the most important genetic drivers, it also exhibits important differences. A personalized approach for patients with this tumor type should consider the clinical relevance of histologic determination of the SRC component and the presence of potentially actionable molecular targets.

Prognostic Immune Effector Signature in Adult Acute Lymphoblastic Leukemia Patients Is Dominated by γδ T Cells.

The success of immunotherapy has highlighted the critical role of the immune microenvironment in acute lymphoblastic leukemia (ALL); however, the immune landscape in ALL remains incompletely understood and most studies have focused on conventional T cells or NK cells. This study investigated the prognostic impact of circulating γδ T-cell alterations using high-dimensional analysis in a cohort of newly diagnosed adult ALL patients (10 B-ALL; 9 Philadelphia+ ALL; 9 T-ALL). Our analysis revealed common alterations in CD8+ T cells and γδ T cells of relapsed patients, including accumulation of early stage differentiation and increased expression of BTLA and CD73. We demonstrated that the circulating γδ T-cell signature was the most discriminating between relapsed and disease-free groups. In addition, Vδ2 T-cell alterations strongly discriminated patients by relapse status. Taken together, these data highlight the role of ɣδ T cells in adult ALL patients, among whom Vδ2 T cells may be a pivotal contributor to T-cell immunity in ALL. Our findings provide a strong rationale for further monitoring and potentiating Vδ2 T cells in ALL, including in the autologous setting.

The influence of lumbo-sacral transitional vertebrae in developmental dysplasia of the hip: a matched pair analysis

Lumbo-sacral transitional vertebrae (LSTV) are the most common congenital alteration of the lumbo-sacral junction and known to significantly influence pelvic anatomy. However, the influence of LSTV on dysplasia of the hip (DDH) and the surgical treatment by periacetabular osteotomy (PAO) remains unknown. We retrospectively examined standardized standing anterior–posterior pelvic radiographs of 170 patients in 185 PAO procedures. Radiographs were examined for LSTV, lateral-central-edge-angle (LCEA), Tönnis-angle (TA), femoral-head-extrusion index (FHEI), and anterior-wall-index (AWI) and posterior-wall-index (PWI). Patients with LSTV were compared to an age- and sex-matched control group. Patient-reported outcome measurements (PROMs) were evaluated pre- and in the mean 63.0 months (range 47–81 months) postoperatively. 43 patients (25.3%) had LSTV. Patients with LSTV had significantly greater PWI (p = 0.025) compared to the matched control group. No significant differences were seen in AWI (p = 0.374), LCEA (p = 0.664), TA (p = 0.667), and FHEI (p = 0.886). Between the two groups, no significant differences were detected in pre- or postoperative PROMs. Due to the increased dorsal femoral head coverage in patients with LSTV and DDH compared to patients with sole DDH, a more pronounced ventral tilting might be performed in those patients with prominent posterior wall sign to avoid anterior undercoverage, which is a significant predictor for premature conversion to hip arthroplasty after PAO. However, anterior overcoverage or acetabular retroversion must be avoided due to the risk of femoroacetabular impingement. Patients with LSTV reported similar functional outcomes and activity after PAO as the control group. Therefore, even for patients with concomitant LSTV, which are frequent with one-fourth in our cohort, PAO is an efficient treatment option to improve clinical symptoms caused by DDH.

Effects of Fructose and Palmitic Acid on Gene Expression in Drosophila melanogaster Larvae: Implications for Neurodegenerative Diseases.

One of the largest health problems worldwide is the development of chronic noncommunicable diseases due to the consumption of hypercaloric diets. Among the most common alterations are cardiovascular diseases, and a high correlation between overnutrition and neurodegenerative diseases has also been found. The urgency in the study of specific damage to tissues such as the brain and intestine led us to use Drosophila melanogaster to study the metabolic effects caused by the consumption of fructose and palmitic acid in specific tissues. Thus, third instar larvae (96 ± 4 h) of the wild Canton-S strain of D. melanogaster were used to perform transcriptomic profiling in brain and midgut tissues to test for the potential metabolic effects of a diet supplemented with fructose and palmitic acid. Our data infer that this diet can alter the biosynthesis of proteins at the mRNA level that participate in the synthesis of amino acids, as well as fundamental enzymes for the dopaminergic and GABAergic systems in the midgut and brain. These also demonstrated alterations in the tissues of flies that may help explain the development of various reported human diseases associated with the consumption of fructose and palmitic acid in humans. These studies will not only help to better understand the mechanisms by which the consumption of these alimentary products is related to the development of neuronal diseases but may also contribute to the prevention of these conditions.

ORAL MANIFESTATIONS OF GRANULOMATOSIS WITH POLYANGIITIS (WEGENER'S GRANULOMATOSIS): A SYSTEMATIC REVIEW

Objective The purpose of this review is to update the oral manifestations of Granulomatosis with polyangiitis. Study Design A systematic review was conducted through a comprehensive electronic search up to and including February 2021, using the search strategy determined in five electronic databases: National Library of Medicine, Washington, D.C. (MEDLINE-PubMed); Embase®; ISI Web of Science; Cochrane; and LIVIVO. Results Ninety-nine published articles were included in this review and reported a total of 126 cases of oral manifestation of GPA. The average age of the patients was 43.66 years and the most common systemic alterations were hypertension, diabetes, and renal failure. The most reported systemic signs were weight loss, fever, pulmonary alterations, and musculoskeletal involvement. Most cases had localized GPA and most had oral involvement in only one location, most prevalently gingiva, followed by oropharynx and hard palate. Predominant lesions were ulcer, followed by strawberry gingivitis, presenting painful symptoms in 73% of cases. Most prevalent biopsy site was gums, followed by palate. Conclusion Oral manifestations of GPA are predominantly symptomatic ulcer and strawberry gingivitis affecting mainly gingiva and oropharynx. Acknowledgements This study was financed by CNPq-Brazil (MCTIC Universal no 408884/2018-5), FAPEMIG and CAPES (Finance Code 001). The purpose of this review is to update the oral manifestations of Granulomatosis with polyangiitis. A systematic review was conducted through a comprehensive electronic search up to and including February 2021, using the search strategy determined in five electronic databases: National Library of Medicine, Washington, D.C. (MEDLINE-PubMed); Embase®; ISI Web of Science; Cochrane; and LIVIVO. Ninety-nine published articles were included in this review and reported a total of 126 cases of oral manifestation of GPA. The average age of the patients was 43.66 years and the most common systemic alterations were hypertension, diabetes, and renal failure. The most reported systemic signs were weight loss, fever, pulmonary alterations, and musculoskeletal involvement. Most cases had localized GPA and most had oral involvement in only one location, most prevalently gingiva, followed by oropharynx and hard palate. Predominant lesions were ulcer, followed by strawberry gingivitis, presenting painful symptoms in 73% of cases. Most prevalent biopsy site was gums, followed by palate. Oral manifestations of GPA are predominantly symptomatic ulcer and strawberry gingivitis affecting mainly gingiva and oropharynx.

AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models

Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder. The pathogenesis of MDD remained unclear, and it may be associated with exposure to different stressors. Most previous studies have focused on molecular changes in a single stress-induced depression model, which limited the identification of the pathogenesis of MDD. The depressive-like behaviors were induced by four well-validated stress models in rats, including chronic unpredictable mild stress, learned helplessness stress, chronic restraint stress and social defeat stress. We applied proteomic and metabolomic to investigate molecular changes in the hippocampus of those four models and revealed 529 proteins and 98 metabolites. Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified differentially regulated canonical pathways, and then we presented a schematic model that simulates AKT and MAPK signaling pathways network and their interactions and revealed the cascade reactions. Further, the western blot confirmed that p-AKT, p-ERK12, GluA1, p-MEK1, p-MEK2, p-P38, Syn1, and TrkB, which were changed in at least one depression model. Importantly, p-AKT, p-ERK12, p-MEK1 and p-P38 were identified as common alterations in four depression models. The molecular level changes caused by different stressors may be dramatically different, and even opposite, between four depression models. However, the different molecular alterations converge on a common AKT and MAPK molecular pathway. Further studies of these pathways could contribute to a better understanding of the pathogenesis of depression, with the ultimate goal of helping to develop or select more effective treatment strategies for MDD.

Integrating differential expression, co-expression and gene network analysis for the identification of common genes associated with tumor angiogenesis deregulation

Angiogenesis is essential for tumor growth and cancer metastasis. Identifying the molecular pathways involved in this process is the first step in the rational design of new therapeutic strategies to improve cancer treatment. In recent years, RNA-seq data analysis has helped to determine the genetic and molecular factors associated with different types of cancer. In this work we performed integrative analysis using RNA-seq data from human umbilical vein endothelial cells (HUVEC) and patients with angiogenesis-dependent diseases to find genes that serve as potential candidates to improve the prognosis of tumor angiogenesis deregulation and understand how this process is orchestrated at the genetic and molecular level.We downloaded four RNA-seq datasets (including cellular models of tumor angiogenesis and ischaemic heart disease) from the Sequence Read Archive. Our integrative analysis includes a first step to determine differentially and co-expressed genes. For this, we used the ExpHunter Suite, an R package that performs differential expression, co-expression and functional analysis of RNA-seq data. We used both differentially and co-expressed genes to explore the human gene interaction network and determine which genes were found in the different datasets that may be key for the angiogenesis deregulation. Finally, we performed drug repositioning analysis to find potential targets related to angiogenesis inhibition.We found that that among the transcriptional alterations identified, SEMA3D and IL33 genes are deregulated in all datasets. Microenvironment remodeling, cell cycle, lipid metabolism and vesicular transport are the main molecular pathways affected. In addition to this, interacting genes are involved in intracellular signaling pathways, especially in immune system and semaphorins, respiratory electron transport and fatty acid metabolism. The methodology presented here can be used for finding common transcriptional alterations in other genetically-based diseases.