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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

OBJECTIVE: Oral supplementation with curcumin demonstrated a beneficial effect on some ocular diseases, including uveitis and macular edema. This study aimed to evaluate the effectiveness and safety of a curcumin formulation with the hydrophilic carrier (CHC; Diabec®, Alfa Intes, Italy) as an adjuvant to standard steroid treatment in adults suffering from acute non-infectious uveitic macular edema (NIUME). PATIENTS AND METHODS: This was a monocenter prospective observational study carried out between January 2019 and May 2020 on consecutive patients with a new diagnosis of NIUME. Patients were treated with standard therapy or with a CHC add-on to standard treatment. The observation period for each patient was 12 months. The Best Corrected Visual Acuity (BCVA) and the Central Macular Thickness (CMT) were the primary outcomes; Foveal Avascular Zone (FAZ) and intraocular pressure (IOP) were also assessed, along with safety data. RESULTS: A total of 43 eyes of 26 patients were analyzed. CHC-treated eyes showed an improvement in mean BCVA from baseline (0.34 logMar) to T6 (0.20 logMar) and T12 (0.19 log- Mar; p≤0.05 and p≤0.01, respectively); CMT decreased from a mean of 320 μm (T0) to 278 μm (T6; p≤0.05) and 272 μm (T12; p≤0.01). A significant improvement of mean BCVA in the CHC group at T6 and T12 was reported compared to the control group (p≤0.01). FAZ and IOP showed no statistically significant variations in both groups. No adverse events were recorded. CONCLUSIONS: CHC as an adjuvant treatment improved the anatomical and functional outcomes, without significant side effects in eyes affected by the recent onset of NIUME, compared to the sole standard therapy. [ABSTRACT FROM AUTHOR]

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.

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.)

Background and Aims: Immediate factor Xa (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases., Methods: We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following acute myocardial infarction (AMI) and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa NOAC and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of AMI patients, we determined CMR based cardiac endpoints under FXa NOAC effects on clinical endpoints in a cohort of AMI patients., Results: Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24h after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced NET formation in mice and patient samples. Proteome and RNA expression analysis of FXa-inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet alpha and dense granule release. Subsequent, thromboinflammatory NET density in thrombi isolated from stroke and myocardial infarction patients was reduced. AMI patients treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment., Conclusions: Long-term FXa inhibition induces anti-thromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Esophageal cancer is the eighth most common cause of cancer-related deaths worldwide. There are two main histological subtypes of esophageal cancer: adenocarcinoma and squamous cell carcinoma. Among the factors associated with the development of esophageal cancer, estrogen receptor beta (ERβ) has been found to have a clinical significance., Aim: To investigate the relationship between ERβ expression and esophageal cancer., Methods: English Medical literature searches were conducted for ERβ expression in patients with esophageal cancer versus healthy controls. Searches were performed up to August 31, 2023, using MEDLINE, PubMed, Embase and Google Scholar. Meta-analysis was performed by using Comprehensive meta-analysis software (Version 4, Biostat Inc., Englewood, NJ, USA). Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated. Heterogeneity was evaluated using Cochrane Q-test, and it was considered present if the Q-test P value was less than 0.10. I 2 statistic was used to measure the proportion of inconsistency in individual studies, with I 2 > 50% representing heterogeneity. We also calculated a potential publication bias., Results: Ten studies representing 11 substudies were selected according to the inclusion criteria. The odds ratio of ERβ expression in fixed effect analysis was 0.448, 95% CI: 0.237 to 0.846, 55.2% lower in esophageal cancer than in normal mucosa. Heterogeneity and inconsistency were low, and no publication bias was demonstrated., Conclusion: This meta-analysis showed that ERβ expression is lower in esophageal cancer biopsy specimens than in healthy controls, this finding may have a significant effect on survival and can lead to new therapeutic avenues.

Background and Objectives: Early in the global COVID-19 pandemic, a concern was raised that potentially high volumes of COVID-19 inpatients in general hospitals might compromise the hospitals' capabilities to maintain high-quality care for routine patients and, thereby, to comply with indicators specifying quality of care. The objective of this study is to evaluate the impact of the surges of COVID-19 inpatients into general hospitals in Israel on the compliance rates for selected quality indicators reported by these hospitals within the Israeli National Program for Quality Indicators (NPQI)., Methods: Compliance rate data were collected from the quality indicators reports made to the NPQI by participating hospitals. COVID-19 inpatient volume data were obtained from the Ministry of Health Digital Technologies and Data Division. Both datasets were analyzed on a week-by-week basis and plotted one alongside the other on a time scale. Association of each quality indicator's compliance rate with the number of COVID-19 inpatients was tested by Pearson's correlation analysis. The study included data from July 1, 2019 through June 30, 2022, spanning the duration of the COVID-19 pandemic in Israel. Five quality indicators included in the study were: Surgical repair of femoral neck fracture within 48 h of admission; Assessment of cerebral ischemic event risk for patients with atrial fibrillation; Duplex carotid ultrasound within 72 h of emergency department admission for patients with suspected transient ischemic attack; Antibiotic prophylaxis for caesarean sections; and Percutaneous coronary intervention within 90 min for patients presenting with ST-elevation myocardial infarction., Results: Compliance rates for five quality indicators, representing different aspects of routine health care, remained steady - even at times with high volumes of COVID-19 inpatients in general hospitals. This lack of effect was prominent throughout the analyzed period, i.e., general hospitals maintained similar compliance rates for all quality indicators both during the surges of COVID-19 patients and between these periods. Statistical analysis showed no correlation between the quality indicators' compliance rates and the number of COVID-19 inpatients., Conclusions: Our findings indicate that high volumes of COVID-19 inpatients in general hospitals did not affect the hospitals' capability to comply with routine health care quality indicators. The results of our study imply that general hospitals in Israel were able to withstand the challenges associated with the care of COVID-19 inpatients while preserving high quality of care for routine patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To establish initial validity of "U-Rate-UE", a single-question scale regarding perceived recovery of the stroke affected upper extremity (UE)., Design: A retrospective longitudinal study of data collected at rehabilitation admission, 6 weeks, and 6 months since stroke., Setting: Stroke rehabilitation and community-based., Participants: A convenience sample of 87 individuals, median (interquartile range) age 71.5 (65-80) years, 15.0 (12-20) days post-stroke., Interventions: Not applicable., Main Outcome Measures: The affected UE was assessed using the Fugl-Meyer Motor Assessment, grip strength, Action Research Arm Test, the Box and Block Test (BBT), and The Rating of Everyday Arm-Use in the Community and Home. Participants also rated how much they perceive that their affected UE recovered from the stroke using U-Rate-UE; 0-100 (no to full recovery). Longitudinal changes in U-Rate-UE ratings were assessed. In addition, at 6 weeks and 6 months post-stroke, the change in BBT was calculated and participants were grouped into achieved/did not achieve the minimal detectable change (MDC). Correlations between U-Rate-UE to the other UE assessments were assessed at all 3 timepoints., Results: Significant changes in U-Rate-UE were seen over time (P<.05). At 6 weeks and 6 months, participants who achieved BBT-MDC rated their recovery significantly higher than participants who did not. U-Rate-UE was moderately-strongly significantly correlated to UE assessments (rho=.61-.85, P<.001)., Conclusions: The U-Rate-UE is supported for use with UE assessments contributing to comprehensive clinical understanding of the recovery of the affected UE in adults post-stroke., (Copyright © 2024 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

RAC1 P29S is the third most prevalent hotspot mutation in sun-exposed melanoma. RAC1 alterations in cancer are correlated with poor prognosis, resistance to standard chemotherapy, and insensitivity to targeted inhibitors. Although RAC1 P29S mutations in melanoma and RAC1 alterations in several other cancers are increasingly evident, the RAC1-driven biological mechanisms contributing to tumorigenesis remain unclear. Lack of rigorous signaling analysis has prevented identification of alternative therapeutic targets for RAC1 P29S -harboring melanomas. To investigate the RAC1 P29S -driven effect on downstream molecular signaling pathways, we generated an inducible RAC1 P29S expression melanocytic cell line and performed RNA-sequencing (RNA-seq) coupled with multiplexed kinase inhibitor beads and mass spectrometry (MIBs/MS) to establish enriched pathways from the genomic to proteomic level. Our proteogenomic analysis identified CDK9 as a potential new and specific target in RAC1 P29S -mutant melanoma cells. In vitro, CDK9 inhibition impeded the proliferation of in RAC1 P29S -mutant melanoma cells and increased surface expression of PD-L1 and MHC Class I proteins. In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade significantly inhibited tumor growth only in melanomas that expressed the RAC1 P29S mutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Gastric cancer (GC) is the fifth most frequent malignancy and the fourth leading cause of worldwide cancer-related death. Despite the usage of multimodal perioperative chemotherapy (pCT), GC progressively gains chemoresistance, thereby, the identification of suitable targets to overcome drug resistance is fundamental. Amongst the potential biomarkers, carbonic anhydrase IX (CAIX) - associated with a poor prognosis of several solid cancers - has gained the most attention. In a cohort of GC patients who received perioperative FLOT (i.e., Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) or FOLFOX (i.e., Leucovorin, 5-Fluouracil, and Oxaliplatin), non-responder patients showed an increased expression of tumor CAIX compared to responder group. Moreover, GC cell lines induced to be resistant to 5-Fluouracil, Paclitaxel, Cisplatin, or the combination of 5-Fluorouracil, Oxaliplatin, and Docetaxel, overexpressed CAIX compared to the control. Accordingly, CAIX-high-expressing GC cells showed increased therapy resistance compared to low-expressing cells. Notably, SLC0111 significantly improved the therapy response of both wild-type and resistant GC cells. Overall, these data suggest a correlation between CAIX and GC drug resistance highlighting the potential of SLC-0111 in re-sensitizing GC cells to pCT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

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).)