Unfavorable Response Research Articles

Genetic and phenotypic parameters for sexual precocity and parasite resistance traits in Nellore cattle.

Indicator traits of sexual precocity are widely used as selection criteria for the genetic improvement of beef cattle; however, the impact of selection for these traits on resistance to endoparasites and ectoparasites is unknown. Therefore, this study aimed to estimate the genetic and phenotypic parameters for indicator traits of sexual precocity and parasite resistance in Nellore cattle. The sexual precocity traits evaluated were probability of first calving (PFC) and scrotal circumference at 12 and 18months of age (SC12 and SC18). The resistance-related traits included tick (TC), gastrointestinal nematode egg (NEC), and Eimeria spp. oocyst (EOC) counts. (Co)variance components were estimated by Bayesian inference using multitrait animal models. The mean heritabilities for PFC, SC12, SC18, TC, NEC, and EOC were 0.23, 0.38, 0.42, 0.14, 0.16, and 0.06, respectively, and suggest that selection will change the mean values of these traits over time. The genetic and phenotypic correlations for most pairs formed by a precocity and a resistance trait were not different from zero, suggesting that selection for sexual precocity traits will not result in changes in resistance traits. Thus, selection for indicator traits of sexual precocity does not elicit unfavorable correlated responses in resistance to endoparasites and ectoparasites, and joint selection aimed at improving these traits can be performed using multitrait selection methods, when necessary.

Student nurses’ experiences of their first clinical placement in intensive care unit: A descriptive phenomenology study

ABSTRACT Background: Technical complexity of patient care and the critical environment at the intensive care unit (ICU) provides a favorable setting for acquiring complicated and comprehensive skills among nursing students. Aims: The current research aims to explore the nursing students’ experiences of their first clinical placement in the ICU and identify the factors that facilitate or hinder their learning. Settings and Design: A study using a qualitative descriptive phenomenological approach was conducted in one of the Oman College of Health Sciences branches. Materials and Methods: A purposive sampling technique was used to recruit 12 Year II students enrolled in the Adult Health Nursing practicum course for in-depth face-to-face interviews. The data were collected in July 2020 following approval of the Ethical Review Board. Statistical Analysis Used: All the interviews were transcribed verbatim and analyzed using Colaizzi’s descriptive phenomenological method. Results: The study results revealed three themes with several subthemes under each. The “experience,” “challenges,” and “the facilitating and hindering factors for learning” were the themes that emerged from the data analysis. Conclusions: Overall, students showed unfavorable responses toward the ICU experience. In addition, the unsupportive interaction with ICU staff contributed significantly to the overall impression. Therefore, strategies to enhance communication and interaction with the ICU staff are essential for a positive ICU learning experience, as students rely on the ICU staff for patient-specific information beyond their academic needs. Therefore, curriculum designers must consider these experiences to facilitate a positive experience in future clinical placements.

Clinicopathologic Impact of NANOG, ZEB1, and EpCAM Biomarkers on Prognosis of Serous Ovarian Carcinoma.

Serous ovarian carcinoma (SOC) is a biologically heterogeneous with different genomic and molecular profiles, beside clinical response to the chemotherapy with subsequent in obstacles in starting unified, acceptable treatments and so we assess immunoexpression of Nanog, ZEB1, and EpCAM in SOC. In this study, the immunoexpression of Nanog, ZEB1, and EpCAM was studied in 60 cases of SOC. Overall survival (OS), disease-free survival (DFS) data and response to chemotherapy were analyzed. NANOG was immunostained in 65% of the cases with a significant association with tumor grade, lymph node metastasis, and FIGO stage (p < 0.001 for each). ZEB1 showed moderate- high expression in 58.3% of the cases with significant up-regulation of ZEB1 expression with SOC grade, nodal metastasis, and SOC FIGO stage (p<0.001). EpCAM revealed high expression in 60% of the cases with significant association with higher grade, nodal metastasis, and advanced stage (p < 0.001 for each). Up-regulation of Nanog was significantly associated with response to chemotherapy, relapse, shorter OS and DFS (p < 0.001 for each). ZEB1 overexpression exhibited a significant association with response to chemotherapy (p= 0.012), relapse, shorter OS and DFS (p<0.001 for each). Moreover, the high EpCAM had a significant association with response to chemotherapy (p= 0.043), relapse (p < 0.001) shorter OS (p=0.006) and DFS (p< 0.001). Up-regulation of Nanog and ZEB-1 and EpCAM perhaps promote an aggressive SOC with a high risk of relapse and unfavorable response to standard chemotherapy regimen.

Thyroid transcription factor 1 (TTF-1) negativity as a predictor of unfavorable response to EGFR-TKI therapy in advanced lung adenocarcinoma patients with EGFR mutations.

The absence of thyroid transcription factor 1 (TTF-1) is associated with a lower frequency of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD). The aim of this study was to assess the impact of TTF-1 expression on the clinical response to EGFR-tyrosine kinase inhibitor (TKI) treatment in patients with advanced LUAD. The data of patients with advanced LUAD who were admitted to the Beijing Tiantan Hospital and Peking University Cancer Hospital (China) between April 2009 and May 2023 was retrospectively analyzed. A total of 227 patients diagnosed with advanced LUAD were included, of which 28.2% (64/227) had TTF-1-negative adenocarcinoma, while 54.6% (124/227) harbored EGFR mutations. Negative TTF-1 expression significantly correlated with male sex (68.8% vs. 42.3%, p < 0.001), history of heavy smoking (57.8% vs. 36.2%, p = 0.003), poorly differentiated tumors (86.5% vs. 43.2%, p < 0.001), and lower frequency of EGFR mutations (26.6% vs. 65.6%, p < 0.001) compared with TTF-1 positivity. Multivariable logistic regression showed that low prevalence of EGFR mutations (p < 0.001) and male sex (p = 0.006) were independent predictive factors for the negative expression of TTF-1. Patients lacking TTF-1 also exhibited worse overall response rate (ORR; 23.5% vs. 54.2%, p = 0.019), disease control rate (DCR; 58.8% vs. 89.7%, p = 0.003), and median progression-free survival (PFS; 2.9 vs. 11.6 months, p < 0.001) following treatment with EGFR-TKIs compared to the TTF-1-positive patients with EGFR mutations. Patients with TTF-1-negative and EGFR-mutant LUAD show a diminished response to EGFR-TKIs.

The influence of deviant advertisements on customer responses: The role of cultural tightness in emerging and developed economies

AbstractCapturing and gaining customers' attention is key to the success of any business. Deviant advertising, including atypical marketing activities that diverge from a social norm, can either be acknowledged due to its attention‐generating character, or is—more often—deemed inappropriate and results in unfavorable consumer responses. This paper reinforces that, in general, ads with deviant content (e.g., the depiction of violence) are evaluated worse as compared to ads portraying nondeviant content. In particular, the role of cultural tightness (i.e., strictness of obeying social norms within society) is empirically examined in analyzing deviant advertisements and its effects on ad attitude and customer responses in an emerging and developed economy. Economic development predominantly affects customer responses of nondeviant ad content (but not deviant ad content). By employing qualitative and quantitative studies, including communicational and observational data collection, this research shows that deviant depictions (vs. nondeviant ads) promote negative attitudes toward ads, and consumers are culturally sensitive, which provides important managerial implications for international marketers.

Hesperidin suppressed metastasis, angiogenesis and tumour growth in Balb/c mice model of breast cancer.

Considering the unfavourable response of breast cancer (BC) to treatment, we assessed the therapeutic potential hesperidin in mice bearing 4T1 BC tumours. Anti-tumour effects were assessed by measuring pathologic complete response (pCR), survival analysis, immunohistochemistry for E-cadherin, VEGF, MMP9, MMP2 and Ki-67, serum measurement of IFNγ and IL-4, and gene expression analysis of CD105, VEGFa, VEGFR2 and COX2. Survival of tumour-bearing mice was the highest in mice receiving a combination of hesperidin and doxorubicin (Dox) (80%) compared to the normal saline (43%), hesperidin 5 (54%), 10 (55.5%), 10 (60.5%) and 40 (66%) mg/kg, and 10 mg/kg Dox-treated (73%) groups (p < 0.0001 for all). Compared to the normal saline group, there was a significant elevation in IFNγ level in the animals receiving 20 (p = 0.0026) and 40 (p < 0.001) mg/kg hesperidin, 10 mg/kg Dox (p < 0.001), and combined hesperidin (20 mg/kg) and Dox (10 mg/kg) (p < 0.001). A significant reduction in the gene expression of CD 105 (p = 0.0106), VEGFa (p < 0.0001), VEGFR2 (p < 0.0001), and Cox2 (p = 0.034) and a significant higher pCR score (p = 0.006) were noticed in mice treated with 10 mg/kg Dox + 20 mg/kg hesperidin compared to those treated with 10 mg/kg Dox alone. Immunohistochemical staining showed significant reductions in Ki-67 (p < 0.001) and VEGF (p < 0.001) and a significant elevation in E-cadherin (p = 0.005) in the 10 mg/kg Dox + 20 mg/kg treatment group than in 10 mg/kg Dox alone group. Hesperidin can be considered as a potentially suitable anti-cancer agent for BC that can synergize with other chemotherapeutics.

The Effects Of Wheat Pill Poisoning (Aluminum Phosphide) Dosage On Arterial Blood Gases And Their Clinical Outcome.

To analyse the effects of aluminum phosphide poisoning dosage on arterial blood gases and the clinical outcome. The cross-sectional study was conducted at the intensive care unit of Mardan Medical Complex, Mardan, Pakistan, from January 2021 to May 2022, and comprised patients of either gender who had attempted suicide using aluminum phosphide. Data was collected using a predesigned questionnaire. Data was analysed using SPSS 26. Of the 116 patients, 42(36.2%) were males and 74(63.8%) were females. There were 75(64.65) survivors; 31(41.33) males and 44(58.66) females with overall mean age 26.30±9.45 years. There were 41(35.35%) non-survivors; 11(26.82%) males and 30(73.18) females with overall mean age 28.21±11.16 years.During hospitalisation, the non- survivors showed drastically decreased levels of all arterial blood gas paramters with severe clinical outcomes (p<0.05). As the number of aluminum phosphide pills increased, the chance of survival decreased (p<0.05). The non-survivors spent an average of 32.51±16.02 hours in hospital (range: 6-59 hours). Patients who ingested more aluminum phosphide pills had more abnormal arterial blood gas parameter with severe clinical outcomes. Also, they had lower chance of survival and unfavourable response to treatment.

SDPS-30 ANALYSIS OF THE BRAIN TUMOR MATRISOME REVEALS CANCER ASSOCIATED FIBROBLASTS PREDICT POOR IMMUNOTHERAPY RESPONSE IN GLIOBLASTOMA PATIENTS

Abstract Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors. Here, we undertook a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures. We found that glioblastoma can be divided into two ECM-based subtypes that are influenced by the presence of cells resembling cancer associated fibroblasts (CAFs) and are conserved across a number of CNS lesions. In glioblastoma, CAF-like cells are correlated with unfavorable response to immune checkpoint blockade and poor patient survival across a subset of CNS tumors. We show that CAF-like cells reside in the perivascular niche, activate chemoattractant signaling pathways to recruit tumor-associated macrophages, and promote glioma stem-like cell phenotype. Our analysis provides insights into mechanisms underlying immunotherapy resistance in glioblastoma and suggests that targeting CAF-like cells may provide an effective approach to improve patient survival in a subset of CNS tumors.

PENERIMAAN BERITA HOAKS MELALUI MEDIA SOSIAL SEBAGAI LITERASI INFORMASI DIKALANGAN REMAJA DI KOTA BANDA ACEH

Based on observations, almost the average student uses a cell phone so that teenagers make social media a trend among these teenagers. Most of them know social media through other peers who attend other schools. The purpose of this research is to encourage youth literacy in the city of Banda Aceh in responding to information on social media, using social media to view information, and teenagers in the city of Banda Aceh in understanding the spread of hoax information on social media. The theory used in this study is the theory of media literacy. This research method uses a qualitative descriptive approach. Research informants consisted of Community Leaders, Academics, Students. Data collection techniques were carried out through observation, interviews and documentation. Based on the research results, it is known that teenagers literacy in the city of Banda Aceh in responding to information on social media can be grouped into two responses. First, students who respond well to news information by observing and understanding and looking for the truth so that they are not mistaken in conveying greetings to other parties. Second, there are students who have unfavorable responses, because they do not pay close attention and understand well, so that they convey news that sometimes is not true to other parties. The understanding of most adolescents in Banda Aceh City regarding the dissemination of information on social media is good, marked by a critical attitude towards understanding it, such as seeking the truth of the same information in other media, so that they are not mistaken in understanding information on social media. However, some students are also not careful in understanding information messages on Social Media, because they are considered to have no benefits for their lives. The understanding of adolescents in Banda Aceh City in spreading hoax information on social media is always careful and not easily provoked by news circulating

Validation of the multidimensional bystander responses to racist hate speech scale and its association with empathy and moral disengagement among adolescents.

Our understanding of how bystanders respond to hate speech is limited. This may be due, in part, to the lack of available measurement tools. However, understanding adolescents' responses to hate speech is critical because this kind of research can support schools in empowering students to exhibit courageous moral behavior. Thus, the purpose of the present study was to investigate the psychometric properties of the newly developed Multidimensional Bystander Responses to Hate Speech Scale (MBRHS) and to explore demographic differences and correlates of bystander behavior in school hate speech. The sample consisted of 3225 seventh to ninth graders from Germany and Switzerland. Exploratory and confirmatory factor analyses supported a model with seven factors. We found that adolescents with immigrant background and boys showed particularly unfavorable response patterns. In addition, our study suggests that empathy is positively correlated with the factors comforting the victim, seeking help at school, and countering hate speech but negatively correlated with helplessness, revenge, reinforcing, and ignoring. Moral disengagement showed the opposite correlational pattern. The findings indicate that the MBRHS is a psychometrically valid and reliable measure that could aid in measuring varied responses to hate speech. In addition, this work highlights the relevance of empathy and moral engagement training in anti-hate speech prevention programs.

NGO Involvement in the Indonesia-EFTA CEPA Negotiations on Palm Oil

Crude palm oil is considered a strategic export commodity for Indonesia because of its contribution to the domestic economy and development so the government will always ensure that agreements related to CPO are included in the discussion of international trade agreements, including the Indonesia EFTA CEPA. However, the agreement related to CPO in Indonesia-EFTA CEPA received an unfavorable response from several national NGOs in Switzerland who are members of The Swiss Palm Oil Coalition. They urged the government of Switzerland to exclude CPO from the free trade agreement. This research aimed to find out the involvement of NGO in Indonesia-EFTA negotiations on palm oil using the conceptual framework of economic diplomacy. The research method used in this paper is descriptive qualitative. The data collection methods used are interview methods, document-based methods, and internet-based methods with data analysis techniques consisting of data reduction, data presentation, and verification and conclusion drawing. Based on the results of the research, it can be concluded that the form of NGO involvement in the palm oil negotiations in the Indonesia-EFTA CEPA can be divided into two, namely NGOs as consulting partners, and NGOs as pressure groups. Keywords: Crude Palm Oil; Economic Diplomacy; Indonesia-EFTA CEPA; NGO

Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma

Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.

Changes in serial multiparametric MRI and FDG-PET/CT functional imaging during radiation therapy can predict treatment response in patients with head and neck cancer

ObjectivesTo test if tumour changes measured using combination of diffusion-weighted imaging (DWI) MRI and FDG-PET/CT performed serially during radiotherapy (RT) in mucosal head and neck carcinoma can predict treatment response.MethodsFifty-five patients from two prospective imaging biomarker studies were analysed. FDG-PET/CT was performed at baseline, during RT (week 3), and post RT (3 months). DWI was performed at baseline, during RT (weeks 2, 3, 5, 6), and post RT (1 and 3 months). The ADCmean from DWI and FDG-PET parameters SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were measured. Absolute and relative change (%∆) in DWI and PET parameters were correlated to 1-year local recurrence. Patients were categorised into favourable, mixed, and unfavourable imaging response using optimal cut-off (OC) values of DWI and FDG-PET parameters and correlated to local control.ResultsThe 1-year local, regional, and distant recurrence rates were 18.2% (10/55), 7.3% (4/55), and 12.7% (7/55), respectively. ∆Week 3 ADCmean (AUC 0.825, p = 0.003; OC ∆ > 24.4%) and ∆MTV (AUC 0.833, p = 0.001; OC ∆ > 50.4%) were the best predictors of local recurrence. Week 3 was the optimal time point for assessing DWI imaging response. Using a combination of ∆ADCmean and ∆MTV improved the strength of correlation to local recurrence (p ≤ 0.001). In patients who underwent both week 3 MRI and FDG-PET/CT, significant differences in local recurrence rates were seen between patients with favourable (0%), mixed (17%), and unfavourable (78%) combined imaging response.ConclusionsChanges in mid-treatment DWI and FDG-PET/CT imaging can predict treatment response and could be utilised in the design of future adaptive clinical trials.Clinical relevance statementOur study shows the complementary information provided by two functional imaging modalities for mid-treatment response prediction in patients with head and neck cancer.Key Points•FDG-PET/CT and DWI MRI changes in tumour during radiotherapy in head and neck cancer can predict treatment response.•Combination of FDG-PET/CT and DWI parameters improved correlation to clinical outcome.•Week 3 was the optimal time point for DWI MRI imaging response assessment.

Pharmacogenomics and the Concept of Personalized Medicine for the Management of Hypertension

Pharmacogenomics and the Concept of Personalized Medicine for the Management of Hypertension

Predicting favorable response to intravenous morphine in pediatric critically ill cardiac patients.

Analgesia and sedation are integral to the care of critically ill children. However, the choice and dose of the analgesic or sedative drug is often empiric, and models predicting favorable responses are lacking. We aimed to compute models to predict a patient's response to intravenous morphine. We retrospectively analyzed data from consecutive patients admitted to the Cardiac Intensive Care Unit (January 2011-January 2020) who received at least one intravenous bolus of morphine. The primary outcome was a decrease in the State Behavioral Scale (SBS) ≥1 point; the secondary outcome was a decrease in the heart rate Z-score (zHR) at 30 min. Effective doses were modeled using logistic regression, Lasso regression, and random forest modeling. A total of 117,495 administrations of intravenous morphine among 8140 patients (median age 0.6 years [interquartile range [IQR] 0.19, 3.3]) were included. The median morphine dose was 0.051 mg/kg (IQR 0.048, 0.099) and the median 30-day cumulative dose was 2.2 mg/kg (IQR 0.4, 15.3). SBS decreased following 30% of doses, did not change following 45%, and increased following 25%. The zHR significantly decreased after morphine administration (median delta-zHR -0.34 [IQR-1.03, 0.00], p < 0.001). The following factors were associated with favorable response to morphine: A concomitant infusion of propofol, higher prior 30-day cumulative dose, being invasively ventilated and/or on vasopressors. Higher morphine dose, higher zHR pre-morphine, an additional analgosedation bolus ±30 min around the index bolus, a concomitant ketamine or dexmedetomidine infusion, and showing signs of withdrawal syndrome were associated with unfavorable response. Logistic regression (area under the receiver operating characteristic [ROC] curve [AUC] 0.900) and machine learning models (AUC 0.906) performed comparably, with a sensitivity of 95%, specificity of 71%, and negative predictive value of 97%. Statistical models identify 95% of effective intravenous morphine doses in pediatric critically ill cardiac patients, while incorrectly suggesting an effective dose in 29% of cases. This work represents an important step toward computer-aided, personalized clinical decision support tool for sedation and analgesia in ICU patients.

Baseline circulating tumor cell (CTC) count as a prognostic marker of overall survival (OS) in metastatic hormone sensitive prostate cancer (mHSPC): Results from SWOG S1216, a phase III randomized trial of androgen deprivation plus orteronel (cyp17 inhibitor) or bicalutamide.

5080 Background: Biomarkers are needed to predict clinical outcomes in mHSPC. We previously reported that baseline CTC counts in S1216 were prognostic of PSA response and disease progression ( ASCO 2020; CCR 2021). However, the trial’s primary overall survival (OS) endpoint was not yet mature at that time. Here we present the final results of S1216 using all available samples to assess the prognostic value of CTC counts for response, progression, OS, and treatment arm interactions. Methods: In S1216, peripheral blood was drawn with informed consent at registration (baseline) and at progression to metastatic castrate resistant prostate cancer (mCRPC). CTCs were enumerated on the FDA-cleared CellSearch platform (Menarini). CTC counts were evaluated for associations with 3 pre-specified trial endpoints: 7-month PSA (7mPSA) ≤ 0.2 ng/ml vs. 0.2–4.0 vs. &gt; 4.0 using a generalized logit model; and progression-free survival (PFS) and OS using Cox regression. Results: From 2014 to 2021, 503 evaluable samples were collected at baseline and 93 at progression. Baseline CTC count was ≥5 in 11.9% of samples, 1-4 in 19.3%, and 0 in 66.8%. Comparing men with 0 vs. ≥5 CTCs at baseline, those with 0 CTCs were significantly more likely to attain a complete PSA response and had significantly lower risk of a PFS event and death after adjusting for clinical covariates (disease burden, bone metastases, age, race, alkaline phosphatase, hemoglobin, PSA, treatment arm). These associations were not modified by treatment arm. Progression CTCs &lt;5 vs. ≥5 also were prognostic of OS (logrank p=0.001), consistent with prior findings in mCRPC. Same-patient CTC counts in matched baseline-progression pairs (n=61) were highly correlated (Spearman p&lt;0.001). Conclusions: CTC count at the start of treatment for mHSPC was highly prognostic of PSA response, PFS, and OS; associations that held in both treatment arms. Moreover, baseline CTC count strongly correlated with progression count, suggesting that mild vs. aggressive disease phenotypes may persist from mHSPC to mCRPC. This evidence from a large prospective phase 3 trial suggests that baseline CTC count is a valuable prognostic marker in men initiating therapy for mHSPC, discriminating those likely to experience favorable vs. unfavorable response and OS. [Table: see text]

Novel genomic alterations and transcriptomic-based tumor microenvironment classification of sarcoma and their impact on treatment decision making.

11547 Background: Sarcomas are rare tumors of mesenchymal origin, with over 50 different histological sarcoma subtypes. The heterogeneous molecular and immunologic characteristics of sarcomas present many challenges for diagnostics and treatment plans. We aim to provide a more comprehensive molecular testing and immune profiling of sarcoma patients. Methods: The cohort consisted of samples from 200 patients diagnosed with sarcomas. WES and whole transcriptome analysis were performed on all samples. Tumor Portrait test identified genomic alterations of sarcomas and classified tumor microenvironment (TME) subtypes. The actual response to immune checkpoint inhibitor (ICI) treatment was determined using RECIST criteria and compared to response predictions by the Tumor Portrait test. Results: Across sarcoma subtypes, the most common mutations were in tumor suppressors including TP53, RB1, CDKN2A, and TSC1/2. We report fusions in 20.5% of cases, with commonly described diagnostic fusions accounting for 34/41 cases. In one case, the detection of the ZC3H7B-BCOR fusion suggested a change in diagnosis from uterine leiomyosarcoma to endometrial stromal sarcoma. Several previously unreported fusions were detected, including potentially targetable ( ARID1A-NUDC, MICAL3-MAPK) and prognostic ( YWHE-CIC) fusions. DNA damage response related genes were mutated in 12% of cases. Other less commonly detected targetable alterations were found in the following genes: MDM2, CDK4, SMARCB1, NF1, PIK3CA, NTRK1-3, FGFR1-4. Transcriptomic-based TME classification found that 52% of patients had an Immune-Enriched (IE) TME, with 26.5% and 25.5% grouped in the IE-Fibrotic and IE-non-Fibrotic subtype, respectively, which we previously showed is associated with good response to ICI treatment. In contrast, 48% of the patients presented with a Fibrotic (F, 30%) or Desert (D, 18%) subtype, are predicted to have a poor response to ICI treatment. Our classification of sarcomas based on TME subtypes conforms well with predicted responses of tumors to ICI therapy found in previous reports. Soft-tissue angiosarcomas, undifferentiated pleomorphic sarcoma, and myxofibrosarcomas presented TMEs of the IE subtype in 75% of cases, significantly more compared to 34% of the bone neoplasm cases, which are known for their favorable and unfavorable response to ICI therapy, respectively (Chi-squared test, p = 0.001). In retrospective chart review, we had response data on 24 patients who received ICI treatment. The disease control rate, defined as CR+PR+SD as best response, was significantly higher in the IE subtype compared to the F/D subtype (85.7% vs 20%, Chi-squared test, p &lt; 0.003). Conclusions: Together, our findings identify actionable and diagnostic alterations in diverse mesenchymal tumors and suggest that ICI treatment may be beneficial in immune-enriched sarcomas.

Insufficient oxygen inhalation during cardiopulmonary resuscitation induces early changes in hemodynamics followed by late and unfavorable systemic responses in post-cardiac arrest rats.

Cardiac arrest (CA) and concomitant post-CA syndrome lead to a lethal condition characterized by systemic ischemia-reperfusion injury. Oxygen (O2 ) supply during cardiopulmonary resuscitation (CPR) is the key to success in resuscitation, but sustained hyperoxia can produce toxic effects post CA. However, only few studies have investigated the optimal duration and dosage of O2 administration. Herein, we aimed to determine whether high concentrations of O2 at resuscitation are beneficial or harmful. After rats were resuscitated from the 10-min asphyxia, mechanical ventilation was restarted at an FIO2 of 1.0 or 0.3. From 10 min after initiating CPR, FIO2 of both groups were maintained at 0.3. Bio-physiological parameters including O2 consumption (VO2 ) and mRNA gene expression in multiple organs were evaluated. The FIO2 0.3 group decreased VO2 , delayed the time required to achieve peak MAP, lowered ejection fraction (75.1 ± 3.3% and 59.0 ± 5.7% with FIO2 1.0 and 0.3, respectively; p < .05), and increased blood lactate levels (4.9 ± 0.2 mmol/L and 5.6 ± 0.2 mmol/L, respectively; p < .05) at 10 min after CPR. FIO2 0.3 group had significant increases in hypoxia-inducible factor, inflammatory, and apoptosis-related mRNA gene expression in the brain. Likewise, significant upregulations of hypoxia-inducible factor and apoptosis-related gene expression were observed in the FIO2 0.3 group in the heart and lungs. Insufficient O2 supplementation in the first 10 min of resuscitation could prolong ischemia, and may result in unfavorable biological responses 2 h after CA. Faster recovery from the impairment of O2 metabolism might contribute to the improvement of hemodynamics during the early post-resuscitation phase; therefore, it may be reasonable to provide the maximum feasible O2 concentrations during CPR.

Excellent response to adalimumab in a patient with Papillon–Lefèvre syndrome: A case report

AbstractPapillon–Lefèvre syndrome (PLS) is a rare autosomal recessive disease that presents clinically with palmoplantar keratoderma and periodontitis and results in early‐onset dental loss. PLS management is difficult. We report a 30‐year‐old female with PLS who had unfavourable response to topical keratolytic creams, oral isotretinoin and narrow‐band ultraviolet‐B (NB‐UVB) phototherapy but showed significant clinical improvement to adalimumab.

Engaging English Audiences in the Dubbing Experience: A Matter of Quality or Habituation?

Although dubbing has traditionally been associated with the so-called dubbing countries, the advent of digitalisation and streaming is nowadays encouraging the consumption of dubbed content across territories unaccustomed to watching foreign fiction with dubs, such as the Anglophone market. Despite the effort put into drawing in a wide and satisfied audience in these countries, an unfavourable response from some viewers has called into question the quality of English dubbed versions and the odds of forging a consolidated dubbing industry in such regions. The main aim of this article is to offer insights into how poor quality and the lack of a long professional tradition might compromise engagement and cinematic illusion and into how the lack of exposure to this mode might have a negative impact on the way the dubbed content is received and enjoyed by English users. The article also intends to discuss the many ways in which quality and habituation affect the dubbing experi­ence. This is done by exploring both the potential constraints that impair the final version and the factors that encourage an amenable attittude to this mode amongst the audience, de­spite their inexperience as dubbing consumers. The conclusions stress the need to enhance English dubbing quality at different levels and the importance of habituation to make dubbing work from a cognitive, linguistic, and prosodic standpoint.