Alteration Events Research Articles

Altered Protein Structures and Neoepitopes in Lupus Neutrophils From Dysregulated Splicing of Messenger RNA.

To test whether messenger RNA (mRNA) splicing is altered in neutrophils from patients with systemic lupus erythematosus (SLE) and can produce neoantigens. RNA sequencing of neutrophils from patients with SLE (n = 15) and healthy donors (n = 12) were analyzed for mRNA splicing using the RiboSplitter pipeline, an event-focused tool based on SplAdder with subsequent translation and protein domain annotation. RNA sequencing from SARS-CoV2-infected individuals was used as an additional comparator. Neutrophils from patients with SLE contained 521 statistically significant altered mRNA splicing events compared with healthy donor neutrophils, many of them affecting important immunologic pathways, myeloid function, transcription factors, and proteins involved in mRNA splicing. A subset of splicing events were only present in SLE samples, and some of them occurred at unannotated splice acceptor or donor sites. Two patients were particularly rich in such events. Only a small number of dysregulated splicing events were more pronounced in patients with active disease or with high type I interferons but were not detected in SARS-CoV2-infected individuals, who also had high type I interferons. Besides causing a range of structural changes, 80 mRNA splice variants exclusive to SLE were predicted to translate into novel amino acid sequences. Peptides derived from these novel amino acid sequences were predicted to bind to the individual patients' class I and II major histocompatibility complex molecules with high affinity. We conclude that aberrant mRNA splicing in SLE has the potential to affect both the function of granulocytes and to generate novel autoantigens.

Phosphoproteomics guides low dose drug combination of cisplatin and silmitasertib against concurrent chemoradiation resistant cervical cancer.

Cisplatin-based concurrent chemoradiotherapy (CCRT) is the standard treatment for cervical patients with locally advanced disease. Despite the improved survival rates and prognosis observed in patients undergoing CCRT, over 30-40% do not achieve complete response and are at risk of locoregional recurrence. Targeting crucial molecules that confer resistance may improve the clinical outcomes of the treatment resistant patient cohort. Herein, we employed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based phosphoproteomic approach to identify the altered phosphophorylation events, activated kinases and dysregulated pathways involved in treatment resistance. We quantified 2531 unique phosphopeptides mapping to 1099 proteins of which 74 proteins were differentially phosphorylated between the cohorts. Pathway analysis revealed dysregulation of the DNA repair pathway and the proteins involved in DNA repair in the non-responder cohort. Additionally, we identified kinase signature associated with CCRT resistance. Kinases such as CSNK2A1, PRKDC, PLK-1, NEK2, ATM and CDK1 are predicted to be activated in non-responders. In particular, we showed that CSNK2A1 is involved in oncogenesis of cervical cancer and pharmacological inhibition led to reduced cell proliferation, migration and colony formation. Moreover, the combination of the CSNK2A1 inhibitor, silmitasertib with cisplatin demonstrated synergism (combination index < 1) and yielded a beneficial reduction in dosage. The dose reduced combination potentially reduced the proliferative, migratory and colony formation ability in vitro. Our findings highlight the potential of phosphoproteomics to identify clinically significant targets and pathways implicated in CCRT resistance. Our study also indicates that combination therapy could serve as an effective treatment strategy to improve the efficacy of patients undergoing CCRT.

Identification of Hydroandradite in CM Carbonaceous Chondrites: A Product of Calc-Silicate Alteration on C-Complex Asteroids

A hydrous Ca-Fe-rich silicate identified as hydroandradite was observed in the ‘Mighei19 type’ carbonaceous (CM) chondrite falls, Shidian and Kolang. This is the first report of hydroandradite occurring within meteorites. Hydroandradite forms through aqueous calc-silicate alteration under specific fluid conditions. Its presence within Shidian and Kolang has implications for interpreting alteration processes within the C-complex asteroid parent bodies of the CM chondrites. To better understand its occurrence, the meteoritic hydroandradite was studied with scanning electron microscopy, electron probe microanalysis, transmission electron microscopy, and Raman spectroscopy. It occurs in four petrographic contexts: layered, perovskite-associated, sulphide-associated, and spheroidal. Kolang has all four morphologies, while only the sulphide-associated occurs in Shidian. In Kolang, hydroandradite was likely produced by replacement of kamacite, Ti-bearing clinopyroxene in calcium- and aluminium-rich inclusions, and secondary magnetite in three distinct alteration events. The formation temperature of meteoritic hydroandradite was estimated to be 100–245°C, based on the mineralogy of the lithologies within which it occurs as well as on its degree of hydration relative to synthetic and terrestrial hydroandradites. Because Kolang and Shidian are the only reported meteorites with hydroandradite to date, they may be from the same parent body.

The source of lithium in connate fluids: Evidence from the geothermal reservoir at Soultz-sous-Forêts, Upper Rhine Graben, France

Geothermal brines in the Upper Rhine Graben have been used as a spa or for salt production since Roman times. Heat and power are generated in geothermal power plants since 2007. Recently, their elevated Li-content has additionally attracted economic interest. This increased interest is in contrast with our understanding of the geological-hydrothermal evolution. We use petrology, major and trace element mineral chemistry and mass balance calculation from drill cores that intersect granitic geothermal reservoir rocks at Soultz-sous-Forêts between Strasbourg and Karlsruhe to shed light on fluid-rock interaction in a reservoir that is actively used for heat and power generation. The alkali feldspar and the two-mica granite in the reservoir have a typical plagioclase, K-feldspar, quartz, biotite and muscovite assemblage with some accessories of titanite, apatite and zircon. Two hydrothermal alteration events are distinguished: (1) albitization of the feldspars; (2) distal replacement of feldspars by sericite and calcite, of biotite by chlorite and titanite; and proximal to hydrothermal veins replacement of the feldspars by sericite and kaolinite. Event 2 feldspar alteration quantitatively releases Pb and Ba to the fluid, whereas Rb, Cs, Sr and Zn show different behaviour depending on whole-rock and mineral composition. Event 2 biotite-chlorite alteration releases Li, Rb, Cs, Sr, Ba, Zn and Pb to the fluid. Mass balance calculation indicates that Si, Fe, Ca, K, Rb, Sr, Zn and Pb contents of the Soultz-sous-Forêts geothermal brine may be explained by fluid-rock interaction in the reservoir. However, the reservoir rock volume that needs to be leached in order to reach recent brine composition varies by several orders of magnitude between the different elements. Many of the elements may be leached during hydrothermal alteration, however in particular Li and Cs require unrealistic fluid-rock ratios of >1/300. These considerations indicate that Na, Ca, Li, Cs and Ba need an additional external source. Based on this, we propose a model where Middle Triassic bittern brines already enriched in Li, Rb, and Cs reacted with the reservoir rocks during hydrothermal event 2 and subsequently mixed with Jurassic-Cretaceous marine water that dissolved evaporites during downward migration. This agrees with Jurassic-Cretaceous illite ages from various sites in the Black Forest and indicates a complex ∼150 m.y. hydrothermal evolution for the brines. There is likely no single source of Li, and it is likely derived from complex fluid-rock interaction with the sedimentary (evaporite) and, less importantly, the crystalline strata of the Upper Rhine Graben. Critical for Li-resource development is the complex hydrothermal history of connate fluids that interacted with sedimentary strata and the preservation in deep-seated reservoirs.

Shorter Leukocyte Telomere Length Is Associated with Increased Major Adverse Cardiovascular Events or Mortality in Patients with Essential Hypertension.

The association between leukocyte telomere length (LTL) alteration and major adverse cardiovascular events (MACE) or mortality in patients with hypertension is still unclear. 20,034 patients with essential hypertension were enrolled from UK biobank. Multivariable COX regression models were performed to assess the association. LTL was shorter in hypertensive patients with MACE compared to those without MACE. Hypertensive patients in the lowest LTL quartile were at higher risk to develop MACE (adjusted HR 1.15 [95%CI 1.02-1.29], vs top LTL quartile, p-trend = 0.03). Similarly, shorter LTL was related with increased mortality (adjusted HR 1.18[95% CI 1.06-1.3], lowest vs top LTL quartile, p-trend < 0.001). This investigation demonstrated that shorter LTL is associated with increased risk of MACE or mortality in patients with essential hypertension, which indicates that LTL may be a potential predictor of prognosis or underlying therapeutic target for hypertension.

A DTI-based radiomics model for predicting epidermal growth factor receptor (EGFR) amplification in adult IDH1-wild glioblastomas.

Molecular alteration events are common in glioblastomas, the isocitrate dehydrogenase (IDH)-wild of which have had poor survival results so far. The progress of radiomics-based model provides novel sights for its preoperatively noninvasive prediction. To develop a radiomics-based model for predicting epidermal growth factor receptor (EGFR) amplification status in IDH1-wild glioblastomas of adults by pretreatment diffusion tensor imaging (DTI). A total of 124 patients with diagnosed glioblastomas were retrospectively collected. Six conventional magnetic resonance imaging (MRI) features of all the tumors were evaluated visually. Patients were divided into the training (n = 87) and the test set (n = 37) with a ratio of 7:3. Radiomics features were extracted from two regions of the glioblastomas, which were the total tumor (ROI_1) and the solid portion of tumor (ROI_2). The radiomics features extracted from the DTI and T1-contrast-enhanced (T1C) images were selected using the least absolute shrinkage and selection operator (LASSO) regression algorithm. Logistic regression analysis was conducted to develop models for EGFR amplification prediction in the training set. The radiomics model based on ROI_1 demonstrated favorable discrimination in both the training (area under the curve [AUC] = 0.86) and the test set (AUC = 0.82) (P < 0.05). Combining the radiomics features and the conventional feature tumor location, no significant improvement of AUCs was achieved (AUC = 0.86 and 0.81). The radiomics model derived from pretreatment DTI may have potential in differentiating the EGFR mutation status in glioblastomas.

Detrital K-feldspar as a novel archive of continental crustal evolution using coupled in situ Rb[sbnd]Sr dating and Pb isotope analysis

Here we present in situ RbSr and Pb isotopic analysis of K-feldspar from the Shap Granite, (Cumbria, UK) and detrital K-feldspar from the associated Shap Wells Conglomerate Formation, to investigate the potential of the detrital K-feldspar record as an archive of crustal composition. We use a unique, collision cell – multi collector inductively coupled plasma tandem mass spectrometer to make the in situ isotope measurements, using ‘chemical resolution’ of 87Rb+ and 204Hg+ isobaric interferences on 87Sr+ and 204Pb+, achieved with SF6 and NH3 reaction gases, respectively. Using this technique, we successfully demonstrate that the majority of detrital K-feldspar RbSr ages, as well as initial Sr and Pb isotope ratios, from the Shap Wells Conglomerate are within uncertainty of those for parental Shap Granite K-feldspar (398 ± 1 Ma, n = 6). Some detrital K-feldspar grains record perturbed RbSr ages, reflecting post depositional alteration events. The majority of samples with disturbed RbSr ages carry distinct petrographic features evident in SEM imaging, prior to in situ dating, which indicates a means to help screen for reliable ages.We further illustrate the potential value of combined RbSr and Pb isotopic information preserved in K-feldspar to estimate the timing and chemical composition of juvenile continental crust formed in the past. Where UPb has been fractionated during juvenile crust formation, the initial Pb isotope ratio provided by the K-feldspar yields model crustal U/Pb (diagnostic of tectonic setting) and extraction age. The contrast in the U/Pb composition of juvenile crust formed in intraplate or subduction settings allows the model U/Pb ratios of the detrital K-feldspars to be used to constrain the style of juvenile crust formation. Additionally, the initial 87Sr/86Sr isotope ratio measured in detrital K-feldspar can be combined with the calculated crustal extraction age and RbSr K-feldspar age to model the Rb/Sr of the juvenile crustal protolith.

On the origin and evolution of deuterium enrichment in type 1 and 2 chondritic organic solids

Rotationally resonant Deuterium Nuclear Magnetic Resonance spectroscopy (D MAS NMR) was applied to IOM isolated from a CR1 chondrite Grosvenor Mountains (GRO) 95577 and a CM2 chondrite (Murchison). It is shown that in IOM D strongly prefers the aliphatic hydrogen reservoir over the aromatic hydrogen reservoir. For GRO 95577, that has a bulk δD of 3303 ‰ (Alexander et al., 2010), the average δD value of the aromatic reservoir is 1740 ± 128 ‰ and the aliphatic reservoir is 4477 ± 105 ‰, i.e., D/H enrichments of 1.27 and 0.64, respectively, relative to the bulk. For Murchison IOM, that has a bulk δD of 811 ‰ (Alexander et al., 2010), the average δD of the aromatic reservoir is 512 ± 88 ‰ and the aliphatic reservoir is 1033 ± 64 ‰ i.e., D/H enrichments of 1.12 and 0.82, respectively, relative to the bulk. D-H exchange between D-enriched water and a type III kerogen reveals nearly equivalent D up take by both aromatics and aliphatics. Laboratory synthesis of IOM-like material in the presence of D2O reveals a high degree of deuteration with a strong preferential deuteration of the aliphatic hydrogen reservoir indicating that the δD of the water during IOM synthesis is the primary determinant of syn-IOM’s δD. The IOM in GRO 95577 and Murchison (FA and H/C × 100) lie on the molecular evolution line as defined by the IOM of the Tagish Lake clasts and Murchison IOM has experienced more molecular evolution relative to that exhibited by GRO 95577 IOM. A forward prediction derived from the D/H ratios for the aliphatic and aromatic hydrogen reservoirs in Murchison and GRO 95577, relative to their bulk D/H ratios, derived from D MAS NMR, is applied to explain the origin of the Tagish Lake trend of δD vs molecular evolution (H/C × 100). The results of this forward prediction suggest that the Tagish Lake isotopic trend results from a combination of molecular evolution (loss of predominantly aliphatic H and D) and partial D-H exchange with D depleted chondritic water during a short-term hydrothermal alteration event. Such events may be faithfully identified in chondritic organic solids and be a common occurrence, but not necessarily revealed in the mineralogy of type 1 and 2 carbonaceous chondrites.

Proteomic Analysis Reveals Physiological Activities of Aβ Peptide for Alzheimer's Disease.

With the rapid progress in deciphering the pathogenesis of Alzheimer's disease (AD), it has been widely accepted that the accumulation of misfolded amyloid β (Aβ) in the brain could cause the neurodegeneration in AD. Although much evidence demonstrates the neurotoxicity of Aβ, the role of Aβ in the nervous system are complex. However, more comprehensive studies are needed to understand the physiological effect of Aβ40 monomers in depth. To explore the physiological mechanism of Aβ, we employed mass spectrometry to investigate the altered proteomic events induced by a lower submicromolar concentration of Aβ. Human neuroblastoma SH-SY5Y cells were exposed to five different concentrations of Aβ1-40 monomers and collected at four time points. The proteomic analysis revealed the time-course behavior of proteins involved in biological processes, such as RNA splicing, nuclear transport and protein localization. Further biological studies indicated that Aβ40 monomers may activate PI3K/AKT signaling to regulate p-Tau, Ezrin and MAP2. These three proteins are associated with dendritic morphogenesis, neuronal polarity, synaptogenesis, axon establishment and axon elongation. Moreover, Aβ40 monomers may regulate their physiological forms by inhibiting the expression of BACE1 and APP via activation of the ERK1/2 pathway. A comprehensive exploration of pathological and physiological mechanisms of Aβ is beneficial for exploring novel treatment.

AcornHRD: an HRD algorithm highly associated with anthracycline-based neoadjuvant chemotherapy in breast cancer in China

PurposeOur study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population.Methods and materialsNinety-six in-house breast cancer (BC) samples and 6 HRD-positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes.ResultsA 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11–81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02–52.36, p = 0.005]).ConclusionUsing the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.

Comprehensive analyses reveal molecular and clinical characteristics of RNA modification writers across 32 cancer types

&lt;p class="MsoNormal" style="text-align: justify;"&gt;&lt;span lang="EN-US" style="font-size: 12pt; font-family: Nunito;"&gt;Adenosine alterations to RNA, which are largely determined by RNA modification writers (RMWs), are critical for cancer growth and progression. These RMWs can catalyze different types of adenosine modifications, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing. These modifications have profound effects on gene expression and function, such as immune response, cell development. Despite this, the clinical effects of RMW interactive genes on these cancers remain largely unclear. A comprehensive analysis of the clinical impact of these epigenetic regulators in pan-cancer requires further comprehensive exploration. Here, we systematically profiled the molecular and clinical characteristics of 26 RMWs across 33 cancer types using multi-omics datasets and validated the expression level of some RMWs in various cancer lines. Our findings indicated that a majority of RMWs exhibited high expression in diverse cancer types, and this expression was found to be significantly associated with poor patient outcomes. In the genetic alterations, the amplification and mutation of RMWs were the dominant alteration events. Consequently, the RNA Modification Writer Score (RMW score) was established as a means to assess the risk of RMWs in pan-cancer. We found that 27 of 33 cancers had significantly higher scores compared with normal tissues, and it was significantly correlated with prognosis. We also evaluated their impact on the tumor microenvironment and the response to immunotherapy and targeted therapy. These findings verified the important role of RMWs in different aspects of cancer biology, and provided biomarkers and personalized therapeutic targets for cancer.&lt;/span&gt;&lt;/p&gt;

Event segmentation in ADHD: neglect of social information and deviant theta activity point to a mechanism underlying ADHD

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is one of the most frequently diagnosed psychiatric conditions in children and adolescents. Although the symptoms appear to be well described, no coherent conceptual mechanistic framework integrates...

Climate Crisis and Agricultural Response: Climate Resilient Crops for Sustainability in Food Production Systems

Climate change encompasses altered levels of temperature and humidity, variability in the rainfall pattern, fluctuations in weather parameters, rise in ambient CO2 levels, emission of greenhouse gases, global warming, etc. that results in extreme events and disasters as cyclones, floods, droughts, salinity, nutrient and heavy metal stress, change in arthropod diversity and emergence of new invasive pests. This results in un-usual effects in agro-ecosystems leading to changes in cropping patterns, crop diversity, and their interaction with biotic and abiotic stress factors, threatening livelihood, food, and nutritional security. Population displacement, declining food productivity, and vulnerable agro-ecosystems are the major consequences of altered meteorological events that occur due to climate change. Therefore, substitution of traditional crops with crops that exhibit resilience to climate crisis is the need of the hour. Smart breeding approaches and precision farming technologies as remote sensing and spectral analysis, artificial intelligence, machine learning, speed breeding, genome analysis, genetic manipulation, gene drive systems, system biology study, omics approaches, etc can make agricultural production climate resilient and sustainable. Response of biofortified crops under changing climate must also be assessed to improve the crop productivity and output.

Screening Splice-Switching Antisense Oligonucleotides in Pancreas-Cancer Organoids.

Aberrant alternative splicing is emerging as a cancer hallmark and a potential therapeutic target. It is the result of dysregulated or mutated splicing factors, or genetic alterations in splicing-regulatory cis-elements. Targeting individual altered splicing events associated with cancer-cell dependencies is a potential therapeutic strategy, but several technical limitations need to be addressed. Patient-derived organoids are a promising platform to recapitulate key aspects of disease states, and to facilitate drug development for precision medicine. Here, we report an efficient antisense-oligonucleotide (ASO) lipofection method to systematically evaluate and screen individual splicing events as therapeutic targets in pancreatic ductal adenocarcinoma organoids. This optimized delivery method allows fast and efficient screening of ASOs, e.g., those that reverse oncogenic alternative splicing. In combination with advances in chemical modifications of oligonucleotides and ASO-delivery strategies, this method has the potential to accelerate the discovery of antitumor ASO drugs that target pathological alternative splicing.

Abstract 1202: Signatures of selection for biallelic inactivation in tumor suppressor genes across cancer types

Abstract Background: The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis, Knudson’s “two hit hypothesis,” posits that loss of both alleles is necessary for TSG inactivation. Many key TSGs accordingly exhibit near universal biallelic loss in associated cancers (e.g., APC in colorectal cancer and RB1 in retinoblastoma). However, because the majority of large-scale cancer genomics studies have utilized non-allele-specific copy number analysis methods, neither the extent of biallelic inactivation across TSGs, nor patterns of selective pressure for biallelic inactivation of TSGs, nor the functional and translational consequences of biallelic inactivation, are well-understood. Methods: Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. We classify TSGs according to their patterns of selection for or against biallelic inactivation across cancer types. Finally, we investigate in detail the association of biallelic status with gene expression and clinical outcome for two TSGs, KEAP1 (in lung adenocarcinoma) and APC (in lung and prostate adenocarcinoma). Results: TSGs largely assort into distinct classes associated with either pan-cancer (Class I) or lineage-specific (Class II) patterns of biallelic loss, while some TSGs, mostly transcription factors, were predominantly monoallelic (Class III/IV). We discover that gene expression and co-mutation patterns indicate selection for biallelic losses in noncanonical contexts, including APC in lung and prostate adenocarcinomas. Selection for biallelic inactivation is also significantly elevated among variants of unknown significance (VUS) of several TSGs, including in KEAP1 in lung adenocarcinoma, nominating these VUS as worthy of in depth functional characterization. Patients with KEAP1 VUS also show similarly poor survival and response to chemoimmunotherapy to patients with known KEAP1 driver mutations, indicating that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles, and that zygosity, rather than variant classification, is prognostic of therapeutic response. Conclusion: TSGs vary significantly in their patterns of biallelic inactivation, and can be classified according to whether and how consistently, across cancer types, they are selected for loss of both copies. Additionally, taking into account the zygosity of TSG alteration events is often necessary to understand their phenotypic and clinical consequences, and can be useful in identifying novel driver events. Citation Format: Mark R. Zucker, Maria A. Perry, Arielle Elkrief, Anton Safonov, Rohit Thummalapalli, Samuel I. Gould, Debyani Chakravarty, Rose Brannon, Marc Ladanyi, Pedram Razavi, Mark T. Donoghue, Yonina R. Murciano-Goroff, Francisco J. Sánchez-Rivera, Yuan Chen, Ronglai Shen, Sarat Chandarlapaty, David B. Solit, Nikolaus Schultz, Michael F. Berger, Adam J. Schoenfeld, Jason Chang, Ed Reznik, Chaitanya Bandlamudi. Signatures of selection for biallelic inactivation in tumor suppressor genes across cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1202.

Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer.

Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance. We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT). All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases. Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.

Pan-caner analysis identifies PSMA7 as a targets for amplification at 20q13.33 in tumorigenesis

The chromosome 20 long arm (20q) is one of the genomic hotspots where copy number alterations frequently occur in multiple types of tumors. However, it remains elusive which genes are implicated in 20q-related tumorigenesis. Here, by querying TCGA and GEO databases, we observed frequent copy number amplification at 20q and the chromosome subband 20q13.33 was amplificated in multiple cancers. Among those genes at 20q13.33, PSMA7 was found with the strongest correlation with cancers. Further analysis revealed that PSMA7 amplification was the most frequent genetic alteration event conferring adverse prognosis in various cancers. Consistent with the strong positive correlation between PSMA7 amplification and gene expression, elevated PSMA7 expression was observed in 20 of 33 types of cancers with a close link to adverse outcomes in certain tumors. In addition, PSMA7 was essential for the growth of almost 1095 cancer lines. Mechanistically, aberrant PSMA7 most probably influenced the proteasome and protease-related pathways to promote tumorigenesis and might be antagonized by several compounds, e.g., Docetaxel in relevant cancers. The current in-depth pan-cancer analysis refines our understanding of the crucial oncogenic role of copy number amplifications at PSMA7 loci at the novel chromosome amplicon 20q13.33 across different tumors.

Future thinking in PTSD: Preliminary evidence for altered event construction

Using a future event fluency task, the current study sought to examine future event construction in PTSD and to identify clinical profiles associated with altered event construction. Thirty-eight trauma exposed war-zone veterans with (n=25) and without (n=13) PTSD generated within one minute as many positive and negative future events as possible in the near and distant future. The PTSD group generated fewer specific, but not generic, events than the no-PTSD group, a difference that was amplified for positive events as a result of comorbid depression. Clinical correlates of event construction varied as a function of event valence.

ALDOA coordinates PDE3A through the β-catenin/ID3 axis to stimulate cancer metastasis and M2 polarization in lung cancer with EGFR mutations

Lung cancer has a high incidence rate and requires more effective treatment strategies and drug options for clinical patients. EGFR is a common genetic alteration event in lung cancer that affects patient survival and drug strategy. Our study discovered aberrant aldolase A (ALDOA) expression and dysfunction in lung cancer patients with EGFR mutations. In addition to investigating relevant metabolic processes like glucose uptake, lactate production, and ATPase activity, we examined multi-omics profiles (transcriptomics, proteomics, and pull-down assays). It was observed that phosphodiesterase 3A (PDE3A) enzyme and ALDOA exhibit correlation, and furthermore, they impact M2 macrophage polarization through β-catenin and downstream ID3. In addition to demonstrating the aforementioned mechanism of action, our experiments discovered that the PDE3 inhibitor trequinsin has a substantial impact on lung cancer cell lines with EGFR mutants. The trequinsin medication was found to decrease the M2 macrophage polarization status and several cancer phenotypes, in addition to transduction. These findings have potential prognostic and therapeutic applications for clinical patients with EGFR mutation and lung cancer.

Inconsistent using FLOOD and Flooding Development of EPA SWMM for Assessing Flood Occurrences in Vulnerable Urban Watershed Considering Extreme Rainfall Events

Urban flood, commonly known as urban water congestion, is a type of water hazard that poses significant challenges for urban residents and water management experts. Chittagong, an essential economic hub in Bangladesh, renowned for its role as a port city, comprises a diverse range of land use, including residential, industrial, and commercial sectors. The Chaktai canal, an important element of Chittagong drainage system, is connected to the Karnaphuli river, playing a vital role in managing drainage by handling a substantial portion of the city water. Therefore, this research evaluated the operational efficiency of a specific drainage network under the influence of altered rainfall events using the Storm Water Management Model (SWMM). Using ArcGIS 10.4, the land use pattern of the area was researched, incorporating data from field surveys and secondary sources. SWMM 5.1 integrated watershed data, and further simulation was carried out to estimate runoff in various sub-catchments and drainage network limitations during heavy rain. During the intense monsoon period, the tool determined the average runoff depth, considering backwater effects and robust tidal surges, resulting in a depth of 3.3m compared to 2.6m in the dry season. This research evaluated the influence of impervious land use changes on urban drainage systems. While meteorological factors alone render drainage network sufficient in dry periods, the outfall shows vulnerability during the rainy season, with an allowance of only 0.7m, jeopardizing the catchment through flood. It contributed a schematic sub-catchment representation, emphasizing that flood events depend on volume runoff and peak flow in urban drainage system. SWMM model was used to illustrate the catchment surface runoff and interconnected node depths via conduits, as well as the current catchment scenario comprehensively.