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Abstract Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, and resistant to both conventional and targeted chemotherapy. Recently, nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease the incidence and mortality of different types of cancers. Here, we investigated the cellular bioactivities of a series of triazolothiadiazine derivatives on HCC, which have been previously reported as potent analgesic/anti-inflammatory compounds. From the initially tested 32 triazolothiadiazine NSAID derivatives, 3 compounds were selected based on their IC50 values for further molecular assays on 9 different HCC cell lines. 7b, which was the most potent compound, induced G2/M phase cell cycle arrest and apoptosis in HCC cells. Cell death was due to oxidative stress-induced JNK protein activation, which involved the dynamic involvement of ASK1, MKK7, and c-Jun proteins. Moreover, 7b treated nude mice had a significantly decreased tumor volume and prolonged disease-free survival. 7b also inhibited the migration of HCC cells and enrichment of liver cancer stem cells (LCSCs) alone or in combination with sorafenib. With its ability to act on proliferation, stemness and the migration of HCC cells, 7b can be considered for the therapeutics of HCC, which has an increased incidence rate of ~ 3% annually.

Background: The mucogingival conditions associated with the recession defects at the mandibular anterior region, not only make plaque control difficult to be performed by the patient but also pose a problem in passively advancing the tissues at the recipient site. This surgical technique is used to treat multiple recession defects in the mandibular anterior region. Materials and Methods: Twenty-five sites in 17 subjects (11 women and 6 men) underwent modified bridge flap and de-epithelized gingival unit graft (d-GUG) as a single-step treatment modality to cover the denuded root surface, as well as increase the width of keratinized gingiva in recession type 1 gingival recession defects in the mandibular anterior region. Results: Nearly 60% of sites in our study showed complete root coverage, with a mean root coverage percentage of 88.08%. Furthermore, keratinized tissue width, keratinized tissue thickness as well as vestibular depth showed statistically significant increases as compared to baseline levels. Conclusion: Thus, the modified bridge flap technique using d-GUG within the limitations of our study design, showed promising results in terms of recession coverage as well as management of the difficult mucogingival conditions at the mandibular anterior region.

Background Accelerating door‐in‐door‐out (DIDO) times at primary stroke centers (PSCs) for patients with large vessel occlusion (LVO) acute ischemic stroke transferred for possible endovascular stroke therapy (EVT) is important to optimize outcomes. Here, we assess whether automated LVO detection coupled with secure communication at non‐EVT performing PSCs improves DIDO time and increases the proportion of patients receiving EVT after transfer. Methods From our prospectively collected multicenter registry, we identified patients with LVO acute ischemic stroke that presented to one of 7 PSCs in the Greater Houston area from January 1, 2021, to February 27, 2022. Noncontrast computed tomography and computed tomographic angiography were performed in all patients at the time of presentation, per standard of care. A machine learning (artificial intelligence [AI]) algorithm trained to detect LVO (Viz.AI) from computed tomographic angiography was implemented at all 7 hospitals. The primary outcome of the study was DIDO at the PSCs and was determined using multivariable linear regression adjusted for sex and on/off hours. Secondary outcomes included likelihood of receiving EVT post‐transfer. Results Among 115 patients who met inclusion criteria, 80 were evaluated pre‐AI and 35 post‐AI. The most common occlusion locations were middle cerebral artery (51.3%) and internal carotid artery (25.2%). There were no substantial differences in demographics or presentation characteristics between the 2 groups. Median time from onset to PSC arrival was 117 minutes (interquartile range, 54–521 minutes). In univariable analysis, patients evaluated at the PSCs after AI implementation had a shorter DIDO time (median difference, 77 minutes; P

Abstract Background Vaccine hesitancy is common among incarcerated populations and, despite vaccination programs, vaccine acceptance within residents remains low, especially within jails. With the goal of assessing the Connecticut DOC’s COVID-19 vaccine program within jails we examined if residents of DOC operated jails were more likely to become vaccinated following incarceration than in the community. Specifically, we conducted a retrospective cohort analysis among people who spent at least one night in a DOC-operated jail between February 2 and November 8, 2021, and were eligible for vaccination at the time of incarceration (intake). We compared the vaccination rates before and after incarceration using an age-adjusted survival analysis with a time-varying exposure of incarceration and an outcome of vaccination. Results During the study period, 3,716 people spent at least one night in jail and were eligible for vaccination at intake. Of these residents, 136 were vaccinated prior to incarceration, 2,265 had a recorded vaccine offer, and 479 were vaccinated while incarcerated. The age-adjusted hazard of vaccination following incarceration was significantly higher than prior to incarceration (12.5; 95% Confidence Intervals: 10.2–15.3). Conclusions We found that residents were more likely to become vaccinated in jail than in the community. Though these findings highlight the utility of vaccination programs within jails, the low level of vaccination in this population speaks to the need for additional program development within jails and the community.

Like other pandemics, COVID-19 also created a huge socioeconomic imbalance and distress in people. Often, every pandemic is characterized as chaotic and complex. Hence, the nature of the virus spread and deaths should be analyzed to prepare for the next similar pandemic. In this analysis, the popular and well-known time series in chaos theory is implemented, and the results are deduced for the states of India. The phase space reconstruction algorithm is implemented, and false nearest neighbor (FNN) method is applied to determine the dimensionality, and also Lyapunov exponent of the time series is estimated. The chaotic nature of COVID-19 cases showed a less severe and low complexity, with the FNN dimension range of 3–5, whereas the COVID-19 deaths showed moderate complexity with FNN dimensions 2–7. Policymakers should take action on medical availability in rural states and control people's movement in highly populated areas.

Due to rapid urban growth and population increase, accurately tracking land use and cover changes (LULC) is vital for predicting outdoor thermal comfort. We used high-res Landsat 8 imagery and on-site weather data, employing a Support Vector Machine (SVM) with PCA to estimate thermal comfort. The PCA addressed variable multicollinearity, and LULC was classified using decision trees. Notable LULC trends emerged. In Hyderabad, built-up areas rose from 37% to 48% (2009–2019) and barren lands fell from 42% to 18%. In Bangalore, built-up areas surged from 25% to 80%, causing vegetation loss (25% to 2%) and reduced barren land (50% to 18%). Jaipur saw a 12% built-up area increase with a slight vegetation uptick. The thermal comfort analysis highlighted Bangalore’s intense urbanization and Jaipur’s limited expansion. Discomfort ranked highest in barren lands, followed by urban, vegetation, and water areas.

Penelitian ini bertujuan untuk mengetahui tingkat kecemasan dan motivasi atlet basket Bangka Belitung saat menjelang pertandingan. Penelitian ini adalah penelitian kuantitatif deskriptif. Alat ukur yang digunakan dalam penelitian ini adalah kuesioner. Responden dalam penelitian yaitu 30 orang atlet basket di wilayah Bangka Belitung. Responden mengisi kuesioner melalui google formulir yang terdiri dari 10 butir pernyataan yang disebarkan lewat whatsapp kepada atlet basket Bangka Belitung. Penelitian ini menggunakan metode survei dan dianalisis secara deskriptif kuantitatif. Berdasarkan hasil penelitian tingkat kecemasan atlet yaitu 30% dan masuk dalam kategori rendah, sedangkan tingkat motivasi atlet yaitu 70% dan masuk dalam kategori tinggi.

BackgroundThe benefit of primary and booster vaccination in people who experienced a prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remains unclear. The objective of this study was to estimate the effectiveness of primary (two-dose series) and booster (third dose) mRNA vaccination against Omicron (lineage BA.1) infection among people with a prior documented infection.Methods and findingsWe conducted a test-negative case-control study of reverse transcription PCRs (RT-PCRs) analyzed with the TaqPath (Thermo Fisher Scientific) assay and recorded in the Yale New Haven Health system from November 1, 2021, to April 30, 2022. Overall, 11,307 cases (positive TaqPath analyzed RT-PCRs with S-gene target failure [SGTF]) and 130,041 controls (negative TaqPath analyzed RT-PCRs) were included (median age: cases: 35 years, controls: 39 years). Among cases and controls, 5.9% and 8.1% had a documented prior infection (positive SARS-CoV-2 test record ≥90 days prior to the included test), respectively. We estimated the effectiveness of primary and booster vaccination relative to SGTF-defined Omicron (lineage BA.1) variant infection using a logistic regression adjusted for date of test, age, sex, race/ethnicity, insurance, comorbidities, social venerability index, municipality, and healthcare utilization. The effectiveness of primary vaccination 14 to 149 days after the second dose was 41.0% (95% confidence interval (CI): 14.1% to 59.4%, p 0.006) and 27.1% (95% CI: 18.7% to 34.6%, p < 0.001) for people with and without a documented prior infection, respectively. The effectiveness of booster vaccination (≥14 days after booster dose) was 47.1% (95% CI: 22.4% to 63.9%, p 0.001) and 54.1% (95% CI: 49.2% to 58.4%, p < 0.001) in people with and without a documented prior infection, respectively. To test whether booster vaccination reduced the risk of infection beyond that of the primary series, we compared the odds of infection among boosted (≥14 days after booster dose) and booster-eligible people (≥150 days after second dose). The odds ratio (OR) comparing boosted and booster-eligible people with a documented prior infection was 0.79 (95% CI: 0.54 to 1.16, p 0.222), whereas the OR comparing boosted and booster-eligible people without a documented prior infection was 0.54 (95% CI: 0.49 to 0.59, p < 0.001). This study's limitations include the risk of residual confounding, the use of data from a single system, and the reliance on TaqPath analyzed RT-PCR results.ConclusionsIn this study, we observed that primary vaccination provided significant but limited protection against Omicron (lineage BA.1) infection among people with and without a documented prior infection. While booster vaccination was associated with additional protection against Omicron BA.1 infection in people without a documented prior infection, it was not found to be associated with additional protection among people with a documented prior infection. These findings support primary vaccination in people regardless of documented prior infection status but suggest that infection history may impact the relative benefit of booster doses.

Background: At present, India is in the decreasing phase of the second wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). But India as a country is in the second position in a high number of confirmed cases (33,678,786) in the world (after the United States of America) and third position in the number of COVID-19 deaths (after the United States and Brazil) at 465,082 deaths. Almost above numbers are dominantly seen in the second wave only. Thus, future long-term projections are required to mitigate the impact. Methods: The conventional SIR model was modified so that a new compartment Q(quarantine) is added to the conventional SIR model to analyze the COVID-19 impact. The parameter optimal control technique was used to fit the curve by estimating the infection, susceptible, etc. Results: The model predicts the cumulative number of cases of 2.6928E7 with a confidence interval of 95%, CI[2.6921E7,2.6935E7], and an accuracy of 99.3% on May 25, 2020(480th day from 30 to 01–2020). The estimated R0 is 1.1475. The model's mean absolute error(EMAE) is 1.79E4, and the root-mean-square error is (ERMSE) is 3.19E4. The future projection are,3.48E7(Lockdown), 3.80E7(periodic-lockdown), 4.52E7(without lockdown). The whole model accuracy is 99%, and projection accuracy is about 94% up to 01-Nov-2021, The goodness of fit value 0.8954. Conclusion: The model is over-estimating corona cases initially and then showed a decreased trend. As the number of days increases, the model accuracy decreases; thus, more control points of the cost function are required to fit the model best.

Presents information on a study conducted to determine the natural coordinate system for phylogenetic trees using a correspondence with the set of perfect matchings in the complete graph. Overview of the use of phylogenetic methodology in the exploration of tree space; Details on perfect matching of phylogenetic trees; Details on the New Hampshire and Newick format of tree representation.

Abstract Background It is accepted that a woman's lifetime risk of developing breast cancer after menopause is reduced by early full term pregnancy and multiparity. This phenomenon is thought to be associated with the development and differentiation of the breast during pregnancy. Methods In order to understand the underlying molecular mechanisms of pregnancy induced breast cancer protection, we profiled and compared the transcriptomes of normal breast tissue biopsies from 71 parous (P) and 42 nulliparous (NP) healthy postmenopausal women using Affymetrix Human Genome U133 Plus 2.0 arrays. To validate the results, we performed real time PCR and immunohistochemistry. Results We identified 305 differentially expressed probesets (208 distinct genes). Of these, 267 probesets were up- and 38 down-regulated in parous breast samples; bioinformatics analysis using gene ontology enrichment revealed that up-regulated genes in the parous breast represented biological processes involving differentiation and development, anchoring of epithelial cells to the basement membrane, hemidesmosome and cell-substrate junction assembly, mRNA and RNA metabolic processes and RNA splicing machinery. The down-regulated genes represented biological processes that comprised cell proliferation, regulation of IGF-like growth factor receptor signaling, somatic stem cell maintenance, muscle cell differentiation and apoptosis. Conclusions This study suggests that the differentiation of the breast imprints a genomic signature that is centered in the mRNA processing reactome. These findings indicate that pregnancy may induce a safeguard mechanism at post-transcriptional level that maintains the fidelity of the transcriptional process.

Abstract Background India has 2.0 million estimated tuberculosis (TB) cases per annum with an estimated 280,000 TB-related deaths per year. Understanding when in the course of TB treatment patients die is important for determining the type of intervention to be offered and crucially when this intervention should be given. The objectives of the current study were to determine in a large cohort of TB patients in India:- i) treatment outcomes including the number who died while on treatment, ii) the month of death and iii) characteristics associated with "early" death, occurring in the initial 8 weeks of treatment. Methods This was a retrospective study in 16 selected Designated Microscopy Centres (DMCs) in Hyderabad, Krishna and Adilabad districts of Andhra Pradesh, South India. A review was performed of treatment cards and medical records of all TB patients (adults and children) registered and placed on standardized anti-tuberculosis treatment from January 2005 to September 2009. Results There were 8,240 TB patients (5183 males) of whom 492 (6%) were known to have died during treatment. Case-fatality was higher in those previously treated (12%) and lower in those with extra-pulmonary TB (2%). There was an even distribution of deaths during anti-tuberculosis treatment, with 28% of all patients dying in the first 8 weeks of treatment. Increasing age and new as compared to recurrent TB disease were significantly associated with "early death". Conclusion In this large cohort of TB patients, deaths occurred with an even frequency throughout anti-TB treatment. Reasons may relate to i) the treatment of the disease itself, raising concerns about drug adherence, quality of anti-tuberculosis drugs or the presence of undetected drug resistance and ii) co-morbidities, such as HIV/AIDS and diabetes mellitus, which are known to influence mortality. More research in this area from prospective and retrospective studies is needed.

Abstract Background A large number of animal and plant genomes have been completely sequenced over the last decade and are now publicly available. Although genomes can be rapidly sequenced, identifying protein-coding genes still remains a problematic task. Availability of protein sequence data allows direct confirmation of protein-coding genes. Mass spectrometry has recently emerged as a powerful tool for proteomic studies. Protein identification using mass spectrometry is usually carried out by searching against databases of known proteins or transcripts. This approach generally does not allow identification of proteins that have not yet been predicted or whose transcripts have not been identified. Results We searched 3,967 mass spectra from 16 LC-MS/MS runs of Anopheles gambiae salivary gland homogenates against the Anopheles gambiae genome database. This allowed us to validate 23 known transcripts and 50 novel transcripts. In addition, a novel gene was identified on the basis of peptides that matched a genomic region where no gene was known and no transcript had been predicted. The amino termini of proteins encoded by two predicted transcripts were confirmed based on N-terminally acetylated peptides sequenced by tandem mass spectrometry. Finally, six sequence polymorphisms could be annotated based on experimentally obtained peptide sequences. Conclusion The peptide sequences from this study were mapped onto the genomic sequence using the distributed annotation system available at Ensembl and can be visualized in the context of all other existing annotations. The strategy described in this paper can be used to correct and confirm genome annotations and permit discovery of novel proteins in a high-throughput manner by mass spectrometry.

Abstract Background The explosion in biological information creates the need for databases that are easy to develop, easy to maintain and can be easily manipulated by annotators who are most likely to be biologists. However, deployment of scalable and extensible databases is not an easy task and generally requires substantial expertise in database development. Results BioBuilder is a Zope-based software tool that was developed to facilitate intuitive creation of protein databases. Protein data can be entered and annotated through web forms along with the flexibility to add customized annotation features to protein entries. A built-in review system permits a global team of scientists to coordinate their annotation efforts. We have already used BioBuilder to develop Human Protein Reference Database http://www.hprd.org, a comprehensive annotated repository of the human proteome. The data can be exported in the extensible markup language (XML) format, which is rapidly becoming as the standard format for data exchange. Conclusions As the proteomic data for several organisms begins to accumulate, BioBuilder will prove to be an invaluable platform for functional annotation and development of customizable protein centric databases. BioBuilder is open source and is available under the terms of LGPL.

Understanding the cell cycle at the single-cell level is crucial for cellular biology and cancer research. While current methods using fluorescent markers have improved the study of adherent cells, non-adherent cells remain challenging. In this study, we addressed this gap by combining a specialized surface to enhance cell attachment, the FUCCI(CA)2 sensor, an automated image analysis pipeline, and a custom machine learning algorithm. This approach enabled precise measurement of cell cycle phase durations in non-adherent cells. This method was validated in acute myeloid leukemia cell lines NB4 and Kasumi-1, which have unique cell cycle characteristics, and we tested the impact of cell cycle-modulating drugs on NB4 cells. Our cell cycle analysis system, which is also compatible with adherent cells, is fully automated and freely available, providing detailed insights from hundreds of cells under various conditions. This report presents a valuable tool for advancing cancer research and drug development by enabling comprehensive, automated cell cycle analysis in both adherent and non-adherent cells., Competing Interests: KH, CS, ES, EC, OE, SP, IN, GB, GF, RC, SM, SR No competing interests declared, (© 2024, Hayatigolkhatmi, Soriani, Soda et al.)

Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Blood vessels are the most important way for cancer cells to survive and diffuse in the body, metastasizing distant organs. During the process of tumor expansion, the neoplastic mass progressively induces modifications in the microenvironment due to its uncontrolled growth, generating a hypoxic and low pH milieu with high fluid pressure and low nutrients concentration. In such a particular condition, reactive oxygen species play a fundamental role, enhancing tumor proliferation and migration, inducing a glycolytic phenotype and promoting angiogenesis. Indeed, to reach new sources of oxygen and metabolites, highly aggressive cancer cells might produce a new abnormal network of vessels independently from endothelial cells, a process called vasculogenic mimicry. Even though many molecular markers and mechanisms, especially in gastric cancer, are still unclear, the formation of such intricate, leaky and abnormal vessel networks is closely associated with patients' poor prognosis, and therefore finding new pharmaceutical solutions to be applied along with canonical chemotherapies in order to control and normalize the formation of such networks is urgent.

Soybeans play a key role in global food security. U.S. soybean yields, which comprise [Formula: see text] of the total soybeans planted in the world, continue to experience unprecedented grain loss due to the soybean cyst nematode (SCN) plant pathogen. SCN remains one of the primary disruptive pests despite the existence of advanced management techniques such as crop rotation and SCN-resistant varieties. SCN detection is a key step in managing this disease; however, early detection is challenging because soybeans do not show any above ground symptoms unless they  are significantly damaged. Direct soil sampling remains the most common method for SCN detection, however, this method has several problems. For example, the threshold damage methods-adopted by most of the laboratories to make recommendations-is not reliable as it does not consider soil pH, N, P, and K values and relies solely on the egg count instead of assessment of the root infection. To overcome the challenges of manual soil sampling methods, deep learning and hyperspectral imaging are important current topics in precision agriculture for plant disease detection and have been proposed as cost-effective and efficient detection methods that can work at scale. We have reviewed more than 150 research papers focusing on soybean cyst nematodes with an emphasis on deep learning techniques for detection and management. First: we describe soybean vegetation and reproduction stages, SCN life cycles, and factors influencing this disease. Second: we highlight the impact of SCN on soybean yield loss and the challenges associated with its detection. Third: we describe direct sampling methods in which the soil samples are procured and analyzed to evaluate SCN egg counts. Fourth: we highlight the advantages and limitations of these direct methods, then review computer vision- and remote sensing-based detection methods: data collection using ground, aerial, and satellite approaches followed by a review of machine learning methods for image analysis-based soybean cyst nematode detection. We highlight the evaluation approaches and the advantages of overall detection workflow in high-performance and big data environments. Lastly, we discuss various management approaches, such as crop rotation, fertilization, SCN resistant varieties such as PI 88788, and SCN's increasing resistance to these strategies. We review machine learning approaches for soybean crop yield forecasting as well as the influence of pesticides, herbicides, and fertilizers on SCN infestation reduction. We provide recommendations for soybean research using deep learning and hyperspectral imaging to accommodate the lack of the ground truth data and training and testing methodologies, such as data augmentation and transfer learning, to achieve a high level of detection accuracy while keeping costs as low as possible., (© 2022. The Author(s).)

Oleocanthal, a minor polar compound in extra-virgin olive (EVO) oil, contains anticancer properties, which should be encouraged in its use in oncology. Gastric Cancer (GC), a very aggressive human cancer, is often diagnosed at advanced stages, when surgery is substituted or supported by chemotherapy (CT). However, CT frequently fails due to the patient's resistance to the treatment. Thus, the aim of this study is to verify whether an OC-enriched EVO oil extract fraction (OCF) may be useful in order to overcome a resistance to GC. We evaluated the OCF effects on an AGS gastric adenocarcinoma cell line wild type (AGS wt) and on its subpopulations resistant to 5-fluorouracil (5FUr), Paclitaxel (TAXr) or cisplatin (CISr). We found that a 60 µM dose of the OCF acts on the AGS wt, 5FUr and TAXr, leading to the cell cycle inhibition and to a ROS production, but not on CISr cells. Resistance of CISr to the OCF seems to be due to higher levels of antioxidant-enzymes that can counteract the OCF-induced ROS production. Moreover, using the OCF plus 5-fluorouracil, Paclitaxel or cisplatin, we found a potentiating effect compared with a mono-treatment in all resistant GC cells, including CISr. In conclusion, the use of the OCF in the management of GC has shown very interesting advantages, opening-up the possibility to evaluate the efficacy of the OCF in vivo, as a valid adjuvant in the treatment of resistant GC.

Only a small proportion of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy and prevents ICB responsiveness by repressing immunogenic double-stranded RNAs (dsRNAs), such as those arising from the dysregulated expression of endogenous retroviral elements (EREs) 1-4 . These dsRNAs trigger an interferon-dependent antitumour response by activating A-form dsRNA (A-RNA)-sensing proteins such as MDA-5 and PKR 5 . Here we show that ADAR1 also prevents the accrual of endogenous Z-form dsRNA elements (Z-RNAs), which were enriched in the 3' untranslated regions of interferon-stimulated mRNAs. Depletion or mutation of ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, which culminated in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumour immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily translatable avenue for rekindling the immune responsiveness of ICB-resistant human cancers., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Because loss of the NF2 tumor suppressor gene results in p21-activated kinase (Pak) activation, PAK inhibitors hold promise for the treatment of NF2-deficient tumors. To test this possibility, we asked if loss of Pak2, a highly expressed group I PAK member, affects the development of malignant mesothelioma in Nf2;Cdkn2a-deficient (NC) mice and the growth properties of NC mesothelioma cells in culture. In vivo, deletion of Pak2 resulted in a markedly decreased incidence and delayed onset of both pleural and peritoneal malignant mesotheliomas in NC mice. In vitro, Pak2 deletion decreased malignant mesothelioma cell viability, migration, clonogenicity, and spheroid formation. RNA-sequencing analysis demonstrated downregulated expression of Hedgehog and Wnt pathway genes in NC;Pak2-/- mesothelioma cells versus NC;Pak2+/+ mesothelioma cells. Targeting of the Hedgehog signaling component Gli1 or its target gene Myc inhibited cell viability and spheroid formation in NC;P+/+ mesothelioma cells. Kinome profiling uncovered kinase changes indicative of EMT in NC;Pak2-/- mesothelioma cells, suggesting that Pak2-deficient malignant mesotheliomas can adapt by reprogramming their kinome in the absence of Pak activity. The identification of such compensatory pathways offers opportunities for rational combination therapies to circumvent resistance to anti-PAK drugs., Implications: We provide evidence supporting a role for PAK inhibitors in treating NF2-deficient tumors. NF2-deficient tumors lacking Pak2 eventually adapt by kinome reprogramming, presenting opportunities for combination therapies to bypass anti-PAK drug resistance., (©2022 American Association for Cancer Research.)

Myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) contribute to cancer-related inflammation and tumor progression. While several myeloid molecules have been ascribed a regulatory function in these processes, the triggering receptors expressed on myeloid cells (TREMs) have emerged as potent modulators of the innate immune response. While various TREMs amplify inflammation, others dampen it and are emerging as important players in modulating tumor progression-for instance, soluble TREM-1 (sTREM-1), which is detected during inflammation, associates with disease progression, while TREM-2 expression is associated with tumor-promoting macrophages. We hypothesized that TREM-1 and TREM-2 might be co-expressed on tumor-infiltrating myeloid cells and that elevated sTREM-1 associates with disease outcomes, thus representing a possibility for mutual modulation in cancer. Using the 4T1 breast cancer model, we found TREM-1 and TREM-2 expression on MDSC and TAM and that sTREM-1 was elevated in tumor-bearing mice in multiple models and correlated with tumor volume. While TREM-1 engagement enhanced TNF, a TREM-2 ligand was detected on MDSC and TAM, suggesting that both TREM could be functional in the tumor setting. Similarly, we detected TREM-1 and Trem2 expression in myeloid cells in the RENCA model of renal cell carcinoma (RCC). We confirmed these findings in human disease by demonstrating the expression of TREM-1 on tumor-infiltrating myeloid cells from patients with RCC and finding that sTREM-1 was increased in patients with RCC. Finally, The Cancer Genome Atlas analysis shows that TREM1 expression in tumors correlates with poor outcomes in RCC. Taken together, our data suggest that manipulation of the TREM-1/TREM-2 balance in tumors may be a novel means to modulate tumor-infiltrating myeloid cell phenotype and function., Competing Interests: Author BR: Research Funding to Institution: Pfizer, Hoffman-LaRoche, Incyte, AstraZeneca, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, BMS, Mirati Therapeutics, Merck, Surface Oncology, Dragonfly Therapeutics, Aravive, Exelixis, Jannsen. Consulting: BMS, Pfizer, GNE/Roche, Aveo, Synthorx, Compugen, Merck, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, GSK, Shionogi, Eisai, Nikang Therapeutics. Stock: PTC therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ford, Gonzalez-Cotto, MacFarlane, Peri, Howard, Subleski, Ruth, Haseebuddin, Al-Saleem, Yang, Rayman, Rini, Linehan, Finke, Weiss, Campbell and McVicar.)

Background: In 2020, the COVID-19 pandemic affected healthcare systems throughout the world, including the management of patients and compliance rates of quality indicators., Objective: To measure the impact in Israel of the COVID-19 pandemic on the indicator-relevant caseload and compliance rates of the quality indicators reported by medical services providers within the Israeli National Program for Quality Indicators (NPQI)., Methods: Data was collected from the reports made to the NPQI by participating hospitals and medical service providers. The indicator results for the number of cases and compliance rates for 2019 were compared to those from 2020. We assessed and compared the results of the quality indicators in general hospitals, geriatric hospitals and departments, psychiatric hospitals and departments, emergency medical services (EMS), and Mother and Baby health centers., Results: We found a decrease in measurable cases in 2020 relative to 2019, especially in geriatric hospitals. In most indicators, compliance rates rose in 2020. Few indicators had lower compliance rates associated with COVID-19 pandemic regulations., Conclusions and Policy Implications: Routine medical activity decreased in Israel in 2020 in comparison to 2019, as reflected by a decrease in cases, but compliance rates were better in most indicators. The results of our study imply that the functioning of healthcare quality measurement programs should not be interrupted during a pandemic. This not only allows measuring of the healthcare system's performance during a crisis, but also may assist in maintaining a high level of healthcare quality., (© 2022. The Author(s).)

Preparation of single-cell suspension from primary tumor tissue can provide a valuable resource for functional, genetic, proteomic, and tumor microenvironment studies. Here, we describe an effective protocol for mouse pancreatic tumor dissociation with further processing of tumor suspension for single-cell RNA sequencing analysis of cellular populations. We further provide an outline of the bioinformatics processing of the data and clustering of heterogeneous cellular populations comprising pancreatic tumors using Common Workflow Language (CWL) pipelines within user-friendly Scientific Data Analysis Platform (https://SciDAP.com). For complete details on the use and execution of this protocol, please refer to Gabitova-Cornell et al. (2020)., Competing Interests: A.K. and A.B. are co-founders of Datirium, LLC., (© 2021 The Author(s).)

Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.

Metabolic reprogramming is a common feature of many human cancers, including acute myeloid leukemia (AML). However, the upstream regulators that promote AML metabolic reprogramming and the benefits conferred to leukemia cells by these metabolic changes remain largely unknown. We report that the transcription factor ATF3 coordinates serine and nucleotide metabolism to maintain cell cycling, survival, and the differentiation blockade in AML. Analysis of mouse and human AML models demonstrate that ATF3 directly activates the transcription of genes encoding key enzymatic regulators of serine synthesis, one-carbon metabolism, and de novo purine and pyrimidine synthesis. Total steady-state polar metabolite and heavy isotope tracing analyses show that ATF3 inhibition reduces de novo serine synthesis, impedes the incorporation of serine-derived carbons into newly synthesized purines, and disrupts pyrimidine metabolism. Importantly, exogenous nucleotide supplementation mitigates the anti-leukemia effects of ATF3 inhibition. Together, these findings reveal the dependence of AML on ATF3-regulated serine and nucleotide metabolism., Competing Interests: Declaration of interests S.P. is currently an employee of Merck Research Laboratories and R. Gabbasov is currently an employee of Carisma Therapeutics. All other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)