bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Cystathionine β-Synthase and 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation, Migration, and Bioenergetics of Murine Breast Cancer Cells
Authors: Santos Sidneia Sousa , Rodrigues Larissa de Oliveira Cavalcanti Peres , Martins Vanessa , Petrosino Maria , Zuhra Karim , Ascenção Kelly , Anand Abhishek , Abdel-Kader Reham Mahmoud , Gad Mohamed Z. , Bourquin Carole , Szabo Csaba
Published: March 2023

Cystathionine β-synthase (CBS), CSE (cystathionine γ-lyase) and 3-mercaptopyruvate sulfurtransferase (3-MST) have emerged as three significant sources of hydrogen sulfide (H2S) in various forms of mammalian cancer. Here, we investigated the functional role of CBS’ and 3-MST’s catalytic activity in the murine breast cancer cell line EO771. The CBS/CSE inhibitor aminooxyacetic acid (AOAA) and the 3-MST inhibitor 2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one (HMPSNE) were used to assess the role of endogenous H2S in the modulation of breast cancer cell proliferation, migration, bioenergetics and viability in vitro. Methods included measurements of cell viability (MTT and LDH assays), cell proliferation and in vitro wound healing (IncuCyte) and cellular bioenergetics (Seahorse extracellular flux analysis). CBS and 3-MST, as well as expression were detected by Western blotting; H2S production was measured by the fluorescent dye AzMC. The results show that EO771 cells express CBS, CSE and 3-MST protein, as well as several enzymes involved in H2S degradation (SQR, TST, and ETHE1). Pharmacological inhibition of CBS or 3-MST inhibited H2S production, suppressed cellular bioenergetics and attenuated cell proliferation. Cell migration was only inhibited by the 3-MST inhibitor, but not the CBS/CSE inhibitor. Inhibition of CBS/CSE of 3-MST did not significantly affect basal cell viability; inhibition of 3-MST (but not of CBS/CSE) slightly enhanced the cytotoxic effects of oxidative stress (hydrogen peroxide challenge). From these findings, we conclude that endogenous H2S, generated by 3-MST and to a lower degree by CBS/CSE, significantly contributes to the maintenance of bioenergetics, proliferation and migration in murine breast cancer cells and may also exert a minor role as a cytoprotectant.
Trace Elements and Ferritin in Pig Saliva: Variations during Fattening, Time of Sampling, Effect of Dirtiness and Stability under Different Storage Conditions
Authors: Ortín-Bustillo Alba , Escribano Damián , Martínez-Subiela Silvia , Tvarijonaviciute Asta , Muñoz-Prieto Alberto , López-Arjona Marina , Cerón José , Tecles Fernando
Published: March 2023

The objective of this study was to evaluate the possible changes of zinc (Zn), copper (Cu), iron (Fe) and ferritin during the entire productive cycle in fattening pigs and at different diurnal sampling times. Moreover, the possible effects of the presence of pen contaminants and storage stability at different temperature conditions were assessed. The analytes changed along the different phases of the fattening productive cycle, showing, in general, higher values at the initial phases. In addition, statistically significant variations were found in Zn and Cu measurements at different sampling times of the day. In the spectrophotometric assays, the values of all analytes significantly increased after adding high concentrations of feces or feed. However, when low concentrations of feces or feed were added, only Cu showed a significant increase. Overall, the salivary levels of Zn, Cu, Fe and ferritin in pigs can change during different fattening phases and the different hours of the day. These analytes were more stable at −80 °C and, if saliva is contaminated with feces or feed, it can lead to an increase in these analytes.
Modeling the Combined Effect of Travelers’ Contrarian Behavior, Learning and Inertia on the Day-to-Day Dynamics of Route Choice
Authors: Meneguzzer Claudio
Published: March 2023

Understanding the many facets of repeated route choice behavior in traffic networks is essential for obtaining accurate flow forecasts and enhancing the effectiveness of traffic management measures. This paper presents a model of the day-to-day evolution of route choices incorporating travelers’ contrarian behavior, learning and inertia. The model is formulated as a discrete-time nonlinear dynamical system, and its properties are investigated analytically and numerically with a focus on the effect of the fraction of individuals adopting a contrarian route choice behavior. The findings of the study indicate that the extent of contrarian behavior may have significant impacts on the attractiveness and stability of network equilibria as well as on global system performance. We show that a properly balanced combination of direct and contrarian subjects can protect the system from instabilities triggered by other behavioral and network features. Our results also suggest that the fixed point stability range may depend to a considerable extent on travelers’ inertia and memory of previous experiences, as well as on the form of the travel cost functions used in the model. The occurrence of contrarian behavior should be explicitly taken into account in the design of traffic management schemes involving the deployment of Advanced Traveler Information Systems (ATISs), as it may act as a mitigating factor against the concentration of choices on the recommended routes. The analytical framework proposed in this paper represents a novel contribution, since contrarian behavior in repeated route choice has been investigated mainly by means of empirical or simulation approaches thus far.
Seasonal Field Calibration of Low-Cost PM2.5 Sensors in Different Locations with Different Sources in Thailand
Authors: Dejchanchaiwong Racha , Tekasakul Perapong , Saejio Apichat , Limna Thanathip , Le Thi-Cuc , Tsai Chuen-Jinn , Lin Guan-Yu , Morris John
Published: March 2023

Low-cost sensors (LCS) have been increasingly deployed to monitor PM2.5 concentrations. More than 1500 LCS have been installed in Thailand to increase public awareness of air quality. However, performance of these sensors has not been systematically investigated. In this study, PM2.5 LCS were co-located next to a PM2.5 federal equivalent method (FEM) reference instrument at three Thai locations—in the north, center and northeast. We evaluated the performance of a PM2.5 LCS (PMS7003, Plantower) to understand the key factors affecting performance, including emission sources, relative humidity, temperature and PM2.5 concentration. Low PM concentration and high humidity levels had a significant impact on performance. Sensors in a high traffic emission area showed low correlation. The unadjusted PM2.5 LCS performance varied with locations. Errors were mainly observed at low concentrations. They significantly underestimated concentrations in congested urban environments. After calibration, accuracy was improved with multiple regression models. The performance of sensors only at Chiang Mai (CM) during the dry season and Ubon Ratchathani (URT) during the dry and wet seasons were acceptable with coefficient of variation: 5.8 ± 4.7–6.8 ± 5.0%, slope: 0.829–0.945, intercept: 1.12–5.49 µg/m3, R2: 0.880–0.934 and RMSE: 4.3–5.1 µg/m3. In the congested area in Bangkok (BKK), they underestimated concentrations of small particles.
Establishment of HFC-134a Emission Inventory in the North China Plain from 1995 to 2020
Authors: Ding Shan , Wu Jing , Wang Jing , Ma Tengfei , Zhang Dayu , Hu Dongmei , Zhang Yueling
Published: March 2023

1,1,1,2-tetrafluoroethane (HFC-134a) is a potent greenhouse gas that can be degraded to produce trifluoroacetic acid (TFA), a degradation product that has an impact on aquatic ecology, so its emission has been a continuous concern worldwide. Existing studies mainly estimate the global- or national-scale emissions of HFC-134a, and there are relatively few studies on regional emissions, all of which used the top-down method. By establishing a regional-scale bottom-up emission inventory and comparing it with the regional-scale top-down estimation results, regional emissions can be verified and their emission characteristics and environmental impacts can be analysed. HFC-134 emissions were estimated for the first time in the North China Plain using the emission factor method, and spatiotemporal characteristics and environmental impacts were analysed for the period of 1995 to 2020. The results showed that the cumulative HFC-134a emissions were 88 (73–103) kt (126 Mt CO2-eq), which have led to an increase in global radiative forcing of 1.1 × 10−3 (0.9 × 10−3–1.3 × 10−3) W m−2, an increase in global surface temperature of 8.9 × 10−4 °C, and a cumulative TFA production of 7.5 (6.2–8.9) kt as of 2020. The major sources of HFC-134a emissions are the refrigeration and air conditioning sector, which involves the automotive air conditioning (MAC), industrial and commercial refrigeration, and air conditioning (ICR) sub-sectors. China joined the Kigali Amendment in 2021 to phase down HFCs and proposed the goal of carbon neutrality by 2060. The North China Plain is a region undergoing rapid economic development, with a relatively high proportion of GDP (29%) and car ownership (23%) in 2020. Additionally, HFC-134a emissions accounted for about 20% of the total emissions in China. Therefore, HFC-134a emissions and their environmental impact on the North China Plain should not be ignored.
Radiative Recombination Plasma Rate Coefficients for Multiply Charged Ions
Authors: Fritzsche Stephan , Maiorova Anna V. , Wu Zhongwen
Published: March 2023

Radiative recombination (RR) plasma rate coefficients are often applied to estimate electron densities and temperatures under quite different plasma conditions. Despite their frequent use, however, these rate coefficients are available only for selected (few-electron) ions and isoelectronic sequences, mainly because of the computational efforts required. To overcome this limitation, we report here a (relativistic) cascade model which helps compute fine-structure and shell-resolved as well as total RR plasma rate coefficients for many, if not most, elements of the periodic table. This model is based on Jac, the Jena Atomic Calculator, and supports studies on how the electron is captured in selected levels of the recombined ion, a relativistic (Maxwellian) electron distribution, or how the multipoles beyond the electric-dipole field in the electron-photon interaction affect the RR rate coefficients and, hence, the ionization and recombination dynamics of hot plasma. As a demonstration of this model, we compute, compare, and discuss different RR plasma rate coefficients for initially helium-like ions, with an emphasis especially on Fe24+ ions.
Challenges and Opportunities for Extracellular Vesicles in Clinical Oncology Therapy
Authors: Lu Shuya , Cui Qingfa , Zheng Huan , Ma Yuan , Kang Yanchun , Tang Ke
Published: March 2023

Extracellular vesicles (EVs) are membrane-bound vesicles that can be released by all cell types. They may have different biogenesis, physical features, and cargo. EVs are important biomarkers for the diagnosis and prediction of many diseases due to their essential role in intercellular communication, their highly variable cargoes, and their accumulation in various body fluids. These natural particles have been investigated as potential therapeutic materials for many diseases. In our previous studies, the clinical usage of tumor-cell-derived microparticles (T-MPs) as a novel medication delivery system was examined. This review summarizes the clinical translation of EVs and related clinical trials, aiming to provide suggestions for safer and more effective oncology therapeutic systems, particularly in biotherapeutic and immunotherapeutic systems.
Adipose Tissue-Derived Components: From Cells to Tissue Glue to Treat Dermal Damage
Authors: Vriend Linda , van der Lei Berend , Harmsen Martin , van Dongen Joris
Published: March 2023

In recent decades, adipose tissue transplantation has become an essential treatment modality for tissue (volume) restoration and regeneration. The regenerative application of adipose tissue has only recently proven its usefulness; for example, the method is useful in reducing dermal scarring and accelerating skin-wound healing. The therapeutic effect is ascribed to the tissue stromal vascular fraction (tSVF) in adipose tissue. This consists of stromal cells, the trophic factors they secrete and the extracellular matrix (ECM), which have immune-modulating, pro-angiogenic and anti-fibrotic properties. This concise review focused on dermal regeneration using the following adipose-tissue components: adipose-tissue-derived stromal cells (ASCs), their secreted trophic factors (ASCs secretome), and the ECM. The opportunities of using a therapeutically functional scaffold, composed of a decellularized ECM hydrogel loaded with trophic factors of ASCs, to enhance wound healing are explored as well. An ECM-based hydrogel loaded with trophic factors combines all regenerative components of adipose tissue, while averting the possible disadvantages of the therapeutic use of adipose tissue, e.g., the necessity of liposuction procedures with a (small) risk of complications, the impossibility of interpatient use, and the limited storage options.
Pelvic Floor Pressures Differ Based on Location in the Pelvis and Body Position: A Cadaver Mode
Authors: Ablove Tova , DeRosa Alexandra , Lewis Steven , Benson Katelyn , Mendel Frank , Doyle Scott
Published: March 2023

Background: The pelvic floor is a bowl-shaped complex of multiple muscles and fascia, which functions to support the pelvic organs, and it aids in controlling continence. In pelvic floor disease, this complex becomes weakened or damaged leading to urinary, fecal incontinence, and pelvic organ prolapse. It is unclear whether the position of the body impacts the forces on the pelvic floor. Purpose: The primary objective of this work is to measure force applied to the pelvic floor of a cadaver in sitting, standing, supine, and control positions. The secondary objective is to map the forces across the pelvic floor. Methods: An un-embalmed female cadaver without pelvic floor dysfunction was prepared for pelvic floor pressure measurement using a pressure sensory array placed on top of the pelvic floor, and urodynamic catheters were placed in the hollow of the sacrum, the retropubic space, and at the vaginal apex. Pressure measurements were recorded with the cadaver in the supine position, sitting cushioned without external pelvic floor support, and standing. Pressure array data were analyzed along with imaging of the cadaver. Together, these data were mapped into a three-dimensional reconstruction of the pressure points in pelvic floor and corresponding pelvic organs. Results: pressures were higher at the symphysis than in the hollow of the sacrum in the standing position. Pressure array measurements were lowest in the standing position and highest in the sitting position. Three-dimensional reconstruction confirmed the location and accuracy of our measurements. Conclusions: The findings of increased pressures behind the symphysis are in line with the higher incidence of anterior compartment prolapse. Our findings support our hypothesis that the natural shape and orientation of the pelvis in the standing position shields the pelvic floor from downward forces of the viscera.
Epigallocatechin Gallate (EGCG), an Active Phenolic Compound of Green Tea, Inhibits Tumor Growth of Head and Neck Cancer Cells by Targeting DNA Hypermethylation
Authors: Agarwal Anshu , Kansal Vikash , Farooqi Humaira , Prasad Ram , Singh Vijay Kumar
Published: March 2023

Head and neck cancers are among the deadliest cancers, ranked sixth globally in rates of high mortality and poor patient prognoses. The prevalence of head and neck squamous cell carcinoma (HNSCC) is associated with smoking and excessive alcohol consumption. Despite several advances in diagnostic and interventional methods, the morbidity of subjects with HNSCC has remained unchanged over the last 30 years. Epigenetic alterations, such as DNA hypermethylation, are commonly associated with several cancers, including HNSCC. Thus, epigenetic changes are considered promising therapeutic targets for chemoprevention. Here, we investigated the effect of EGCG on DNA hypermethylation and the growth of HNSCC. First, we assessed the expression levels of global DNA methylation in HNSCC cells (FaDu and SCC-1) and observed enhanced methylation levels compared with normal human bronchial epithelial cells (NHBE). Treatment of EGCG to HNSCC cells significantly inhibited global DNA hypermethylation by up to 70–80% after 6 days. Inhibition of DNA hypermethylation in HNSCC cells was confirmed by the conversion of 5-methylcytosine (5-mc) into 5-hydroxy methylcytosine (5hmC). DNA methyltransferases regulate DNA methylation. Next, we checked the effect of EGCG on the expression levels of DNA methyltransferases (DNMTs) and DNMT activity. Treatment of EGCG to HNSCC cells significantly reduced DNMT activity to 60% in SCC-1 and 80% in FaDu cells. The protein levels of DNMT3a and DNMT3b were downregulated in both cell lines after EGCG treatment. EGCG treatment to HNSCC cells reactivated tumor suppressors and caused decreased cell proliferation. Our in vivo study demonstrated that administration of EGCG (0.5%, w/w) as a supplement within an AIN76A diet resulted in inhibition of tumor growth in FaDu xenografts in nude mice (80%; p < 0.01) compared with non-EGCG-treated controls. The growth inhibitory effect of dietary EGCG on the HNSCC xenograft tumors was associated with the inhibition of DNMTs and reactivation of silenced tumor suppressors. Together, our study provides evidence that EGCG acts as a DNA demethylating agent and can reactivate epigenetically silenced tumor suppressors to inhibit the growth of HNSCC cells.
Electrochemistry Test Strip as Platform for In Situ Detection of Blood Levels of Antipsychotic Clozapine in Finger-Pricked Sample Volume
Authors: Senel Mehmet
Published: March 2023

With the increasing number of patients suffering from Parkinson’s disease, the importance of measuring drug levels in patient body fluids has increased exponentially, particularly for the drug clozapine. There is a growing demand for real-time analysis of biofluids on a single low-cost platform in ultra-low fluid volumes with robustness. This study aims to measure the level of clozapine (Clz) with a portable potentiostat using a practical approach. For this purpose, we developed an inexpensive, portable platform via electrochemistry on a commercial glucose test strip (CTS). CTSs were first modified by removing the enzyme mixture from the surface of the sensing zone, which was followed by modification with Multi walled carbon nanotube (MWCNT) and Nafion. The electrochemical characteristics of CTS electrodes were investigated using cyclic voltammetry (CV) and differential voltammetry (DPV) techniques. The designed sensor displayed decent linear range, detection limit, reproducibility, and reusability results. A linear dynamic range of 0.1–5 μM clozapine was observed under optimized conditions with a good sensitivity (1.295 μA/μM) and detection limit (83 nM). Furthermore, the designed sensing electrode was used to measure the amount of Clz in real samples.
Electroacupuncture Alleviates Depressive-like Behavior by Modulating the Expression of P2X7/NLRP3/IL-1β of Prefrontal Cortex and Liver in Rats Exposed to Chronic Unpredictable Mild Stress
Authors: Pang Fang , Yang Yunhao , Huang Siqin , Yang Zhixue , Zhu Zhengwei , Liao Dongmei , Guo Xiao , Zhou Min , Li Yi , Tang Chenglin
Published: March 2023

Depression is a complex clinical disorder associated with poor outcomes. Electroacupuncture (EA) has been demonstrated to have an important role in both clinical and pre-clinical depression investigations. Evidence has suggested that the P2X7 receptor (P2X7R), NLRP3, and IL-1β play an important role in depressive disorder. Our study is aimed at exploring the role of EA in alleviating depression-like behaviors in rats. We therefore investigated the effects of EA on the prefrontal cortex and liver of rats subjected to chronic unpredictable mild stress (CUMS) through behavior tests, transmission electron microscopy, Nissl staining, HE staining, immunohistochemistry and Western blotting. Five weeks after exposure to CUMS, Sprague-Dawley (SD) rats showed depression-like behavior. Three weeks after treatment with brilliant blue G (BBG) or EA, depressive symptoms were significantly improved. Liver cells and microglia showed regular morphology and orderly arrangement in the BBG and EA groups compared with the CUMS group. Here we show that EA downregulated P2X7R/NLRP3/IL-1β expression and relieved depression-like behavior. In summary, our findings demonstrated the efficacy of EA in alleviating depression-like behaviors induced by CUMS in rats. This suggests that EA may serve as an adjunctive therapy in clinical practice, and that P2X7R may be a promising target for EA intervention on the liver–brain axis in treatment of depression.
Intraparenchymal and Subarachnoid Hemorrhage in Stereotactic Electroencephalography Caused by Indirect Adjacent Arterial Injury: Illustrative Case
Authors: Kawashima Toshiyuki , Uda Takehiro , Koh Saya , Yindeedej Vich , Ishino Noboru , Ichinose Tsutomu , Arima Hironori , Sakuma Satoru , Goto Takeo
Published: March 2023

The complication rate of stereotactic electroencephalography (SEEG) is generally low, but various types of postoperative hemorrhage have been reported. We presented an unusual hemorrhagic complication after SEEG placement. A 20-year-old man presented with suspected frontal lobe epilepsy. We implanted 11 SEEG electrodes in the bilateral frontal lobes and the left insula. Computed tomography after implantation showed intraparenchymal hemorrhage in the left temporal lobe and insula and subarachnoid hemorrhage in the left Sylvian cistern. Later, the point of vessel injury was revealed from the identification of a pseudoaneurysm, but this location was not along the planned or actual electrode trajectory. The cause of hemorrhage was suggested to be indirect injury from stretching of the arachnoid trabeculae by the puncture needle.
“Pandemic Fatigue” in South America: A Multi-Center Report from Argentina, Bolivia, Paraguay, Peru, and Uruguay
Authors: Torales Julio , González-Urbieta Israel , Barrios Iván , Waisman-Campos Marcela , Terrazas-Landivar Alexandra , Viola Laura , Caycho-Rodríguez Tomás , Melgarejo Osvaldo , Navarro Rodrigo , García Oscar , Almirón-Santacruz José , Castaldelli-Maia João Mauricio , Ventriglio Antonio
Published: March 2023

The COVID-19 pandemic has had a heavy impact on daily life, leading to physical and psychosocial consequences. Nowadays, clinicians and health researchers are particularly interested in describing and facing the long-term effects of COVID-19, also known as “long-COVID syndrome”. Pandemic fatigue has been defined as a cluster of demotivation, tiredness, and psychological effects that emerge gradually over time after the infection or through the adoption of the recommended measures to combat it. In this study, we report the findings of a large survey conducted in South America involving 1448 participants (mean age: 33.9 ± 11.2 years old) from Argentina, Bolivia, Uruguay, Peru, and Paraguay. An online survey was launched through the common social media based on a specific assessment aimed to detect the prevalence of pandemic fatigue and associated factors. Socio-demographic characteristics, medical, and personal information were collected; the Pandemic Fatigue Scale (PFS) and the Coronavirus Anxiety Scale (CAS) were also administered. We found mid-levels of pandemic fatigue among respondents (21.7 ± 7.95 score at PFS) as well as significant anxiety related to the COVID-19 pandemic (1.56 ± 2.76 score at CAS). In addition, pandemic fatigue was significantly associated with the experience of the loss of a relative/friend due to COVID-19, anxiety related to the infection, and reliance on social media as a primary source of information on the pandemic. Vaccination significantly reduced the levels of fatigue among respondents. Our findings may add to the international debate regarding the long-term health consequences of the COVID-19 pandemic and strategies to manage them in the general population of South America.
The Mucin Family of Proteins: Candidates as Potential Biomarkers for Colon Cancer
Authors: Cox Kristin E. , Liu Shanglei , Lwin Thinzar M. , Hoffman Robert M. , Batra Surinder K. , Bouvet Michael
Published: March 2023

Mucins (MUC1–MUC24) are a family of glycoproteins involved in cell signaling and barrier protection. They have been implicated in the progression of numerous malignancies including gastric, pancreatic, ovarian, breast, and lung cancer. Mucins have also been extensively studied with respect to colorectal cancer. They have been found to have diverse expression profiles amongst the normal colon, benign hyperplastic polyps, pre-malignant polyps, and colon cancers. Those expressed in the normal colon include MUC2, MUC3, MUC4, MUC11, MUC12, MUC13, MUC15 (at low levels), and MUC21. Whereas MUC5, MUC6, MUC16, and MUC20 are absent from the normal colon and are expressed in colorectal cancers. MUC1, MUC2, MUC4, MUC5AC, and MUC6 are currently the most widely covered in the literature regarding their role in the progression from normal colonic tissue to cancer.
Recurrent Esthesioneuroblastoma: Long-Term Outcomes of Salvage Therapy
Authors: Ni Garrett , Pinheiro-Neto Carlos D. , Iyoha Ehiremen , Van Gompel Jamie J. , Link Michael J. , Peris-Celda Maria , Moore Eric J. , Stokken Janalee K. , Gamez Mauricio , Choby Garret
Published: March 2023

Introduction: Esthesioneuroblastoma (ENB) is a rare malignant neoplasm arising from the olfactory epithelium of the cribriform plate. Although survival is excellent with a reported 5-year overall survival (OS) of 82%, recurrence is frequent and occurs in 40–50% of cases. This study investigates the characteristics of ENB recurrence and the subsequent prognosis of patients with recurrence. Methods: The clinical records of all patients diagnosed as having ENB with subsequent recurrence at a tertiary hospital from 1 January 1960 to 1 January 2020 were retrospectively reviewed. Overall survival (OS) and progression-free survival (PFS) were reported. Results: A total of 64 out of 143 ENB patients had recurrences. In total, 45 out of 64 recurrences met the inclusion criteria and were included in this study. From these, 10 (22%) had a sinonasal recurrence, 14 (31%) had an intracranial recurrence, 15 (33%) had a regional recurrence, and 6 (13%) had a distal recurrence. The average interval from initial treatment to recurrence was 4.74 years. There were no differences in rates of recurrence with respect to age, sex, or types of surgery (endoscopic, transcranial, lateral rhinotomy, and combined). The time to recurrence was shorter for Hyams grades 3 and 4 compared to Hyams grades 1 and 2 (3.75 years vs. 5.70 years, p < 0.05). Patients with recurrence limited to the sinonasal region had a lower overall primary Kadish stage compared to recurrences beyond the sinonasal region (2.60 vs. 3.03, p < 0.05). A total of 9 (20%) out of 45 patients developed secondary recurrence. Following recurrence, the subsequent 5-year OS and PFS were 63 and 56%, respectively. The mean time to secondary recurrence after treatment of the primary recurrence was 32 months, which was significantly shorter than the time to primary recurrence (32 months vs. 57 months, p = 0.048). The mean age of the secondary recurrence group is significantly older than the primary recurrence group (59.78 years vs. 50.31 years, p = 0.02). No statistically significant differences were observed between the secondary recurrence group and the recurrence group in terms of their overall Kadish stages or Hyams grades. Conclusions: Following an ENB recurrence, salvage therapy appears to be an effective therapeutic option with a subsequent 5-year OS of 63%. However, subsequent recurrences are not infrequent and may require additional therapy.
Differential Impact of a Multicomponent Goals-of-Care Program in Patients with Hematologic and Solid Malignancies
Authors: Hui David , Ahmed Sairah , Nortje Nico , George Marina , Andersen Clark R. , Wilson Kaycee , Urbauer Diana , Flowers Christopher , Bruera Eduardo
Published: March 2023

We recently reported that an interdisciplinary multicomponent goals-of-care (myGOC) program was associated with an improvement in goals-of-care (GOC) documentation and hospital outcomes; however, it is unclear if the benefit was uniform between patients with hematologic malignancies and solid tumors. In this retrospective cohort study, we compared the change in hospital outcomes and GOC documentation before and after myGOC program implementation between patients with hematologic malignancies and solid tumors. We examined the change in outcomes in consecutive medical inpatients before (May 2019–December 2019) and after (May 2020–December 2020) implementation of the myGOC program. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included GOC documentation. In total, 5036 (43.4%) patients with hematologic malignancies and 6563 (56.6%) with solid tumors were included. Patients with hematologic malignancies had no significant change in ICU mortality between 2019 and 2020 (26.4% vs. 28.3%), while patients with solid tumors had a significant reduction (32.6% vs. 18.8%) with a significant between-group difference (OR 2.29, 95% CI 1.35, 3.88; p = 0.004). GOC documentation improved significantly in both groups, with greater changes observed in the hematologic group. Despite greater GOC documentation in the hematologic group, ICU mortality only improved in patients with solid tumors.
Higher Age (≥60 Years) Increases the Risk for Adverse Events during Autologous Hematopoietic Stem Cell Transplantation
Authors: Haubitz Monika , von Petersdorff Vittoria S. , Helsen Ingrid , Brunold Claudio , Oppliger Leibundgut Elisabeth , Baerlocher Gabriela M.
Published: March 2023

Autologous hematopoietic stem cell transplantation (autoHSCT) is a standard of care for patients with hemato-oncologic diseases. This procedure is highly regulated, and a quality assurance system needs to be in place. Deviations from defined processes and outcomes are reported as adverse events (AEs: any untoward medical occurrence temporally associated with an intervention that may or may not have a causal relationship), including adverse reactions (ARs: a response to a medicinal product which is noxious and unintended). Only a few reports on AEs cover the procedure of autoHSCT from collection until infusion. Our aim was to investigate the occurrence and severity of AEs in a large data set of patients who were treated by autoHSCT. In this retrospective, observational, single-center study on 449 adult patients during the years 2016–2019, AEs occurred in 19.6% of the patients. However, only 6.0% of patients had ARs, which is a low rate compared to the percentages (13.5–56.9%) found in other studies; 25.8% of the AEs were serious and 57.5% were potentially serious. Larger leukapheresis volumes, lower numbers of collected CD34+ cells and larger transplant volumes significantly correlated with the occurrence and number of AEs. Importantly, we found more AEs in patients >60 years (see graphical abstract). By preventing potentially serious AEs of quality and procedural issues, AEs could be reduced by 36.7%. Our results provide a broad view on AEs and point out steps and parameters for the potential optimization of the autoHSCT procedure, especially in elderly patients.
Applications of Machine Learning in Palliative Care: A Systematic Review
Authors: Vu Erwin , Steinmann Nina , Schröder Christina , Förster Robert , Aebersold Daniel M. , Eychmüller Steffen , Cihoric Nikola , Hertler Caroline , Windisch Paul , Zwahlen Daniel R.
Published: March 2023

Objective: To summarize the available literature on using machine learning (ML) for palliative care practice as well as research and to assess the adherence of the published studies to the most important ML best practices. Methods: The MEDLINE database was searched for the use of ML in palliative care practice or research, and the records were screened according to PRISMA guidelines. Results: In total, 22 publications using machine learning for mortality prediction (n = 15), data annotation (n = 5), predicting morbidity under palliative therapy (n = 1), and predicting response to palliative therapy (n = 1) were included. Publications used a variety of supervised or unsupervised models, but mostly tree-based classifiers and neural networks. Two publications had code uploaded to a public repository, and one publication uploaded the dataset. Conclusions: Machine learning in palliative care is mainly used to predict mortality. Similarly to other applications of ML, external test sets and prospective validations are the exception.
CD22 Exon 12 Deletion as an Independent Predictor of Poor Treatment Outcomes in B-ALL
Authors: Qazi Sanjive , Uckun Fatih M.
Published: March 2023

We previously reported a splicing defect (CD22ΔE12) associated with the deletion of exon 12 of the inhibitory co-receptor CD22 (Siglec-2) in leukemia cells from patients with CD19+ B-precursor acute lymphoblastic leukemia (B-ALL). CD22ΔE12 causes a truncating frameshift mutation and yields a dysfunctional CD22 protein that lacks most of the cytoplasmic domain required for its inhibitory function, and it is associated with aggressive in vivo growth of human B-ALL cells in mouse xenograft models. Although CD22ΔE12 with selective reduction of CD22 exon 12 (CD22E12) levels was detected in a high percentage of newly diagnosed as well as relapsed B-ALL patients, its clinical significance remains unknown. We hypothesized that B-ALL patients with very low levels of wildtype CD22 would exhibit a more aggressive disease with a worse prognosis because the missing inhibitory function of the truncated CD22 molecules could not be adequately compensated by competing wildtype CD22. Here, we demonstrate that newly diagnosed B-ALL patients with very low levels of residual wildtype CD22 (“CD22E12low”), as measured by RNAseq-based CD22E12 mRNA levels, have significantly worse leukemia-free survival (LFS) as well as overall survival (OS) than other B-ALL patients. CD22E12low status was identified as a poor prognostic indicator in both univariate and multivariate Cox proportional hazards models. CD22E12low status at presentation shows clinical potential as a poor prognostic biomarker that may guide the early allocation of risk-adjusted, patient-tailored treatment regimens and refine risk classification in high-risk B-ALL.
The Change in Social Eating over Time in People with Head and Neck Cancer Treated with Primary (Chemo)Radiotherapy: The Role of Swallowing, Oral Function, and Nutritional Status
Authors: Ninfa Aurora , Jansen Femke , Delle Fave Antonella , Lissenberg-Witte Birgit I. , Pizzorni Nicole , Baatenburg de Jong Robert J. , Lamers Femke , Leemans C. René , Takes Robert P. , Terhaard Christianus H. J. , Schindler Antonio , Verdonck-de Leeuw Irma M.
Published: March 2023

This study aimed at investigating the change in social eating problems from diagnosis to 24 months after primary (chemo)radiotherapy and its associations with swallowing, oral function, and nutritional status, in addition to the clinical, personal, physical, psychological, social, and lifestyle dimensions. Adult patients from the NETherlands QUality of life and BIomedical Cohort (NET-QUBIC) treated with curative intent with primary (chemo)radiotherapy for newly-diagnosed HNC and who provided baseline social eating data were included. Social eating problems were measured at baseline and at 3-, 6-, 12-, and 24-month follow-up, with hypothesized associated variables at baseline and at 6 months. Associations were analyzed through linear mixed models. Included patients were 361 (male: 281 (77.8%), age: mean = 63.3, SD = 8.6). Social eating problems increased at the 3-month follow-up and decreased up to 24 months (F = 33.134, p < 0.001). The baseline-to-24 month change in social eating problems was associated with baseline swallowing-related quality of life (F = 9.906, p < 0.001) and symptoms (F = 4.173, p = 0.002), nutritional status (F = 4.692, p = 0.001), tumor site (F = 2.724, p = 0.001), age (F = 3.627, p = 0.006), and depressive symptoms (F = 5.914, p < 0.001). The 6–24-month change in social eating problems was associated with a 6-month nutritional status (F = 6.089, p = 0.002), age (F = 5.727, p = 0.004), muscle strength (F = 5.218, p = 0.006), and hearing problems (F = 5.155, p = 0.006). Results suggest monitoring social eating problems until 12-month follow-up and basing interventions on patients’ features.
Association between Age at Helicobacter pylori Eradication and the Risk of Gastric Cancer Stratified by Family History of Gastric Cancer: A Nationwide Population-Based Study
Authors: Jung Yoon Suk , Tran Mai Thi Xuan , Song Huiyeon , Park Boyoung , Moon Chang Mo
Published: March 2023

Introduction: This study compares the risk of GC according to age at H. pylori eradication, stratified based on the presence of family history of GC using a population-based large cohort. Method: We analyzed individuals who underwent GC screening between 2013 and 2014 and received H. pylori eradication therapy before screening. Results: Among 1,888,815 H. pylori-treated patients, 2610/294,706 and 9332/1,594,109 patients with and without a family history of GC, respectively, developed GC. After adjusting for confounders, including age at screening, the adjusted hazard ratios (95% confidence intervals) for GC comparison, 70–74, 65–69, 60–64, 55–59, 50–54, 45–49, and <45 years with ≥75 years at H. pylori eradication were 0.98 (0.79–1.21), 0.88 (0.74–1.05), 0.76 (0.59–0.99), 0.62 (0.44–0.88), 0.57 (0.36–0.90), 0.38 (0.22–0.66), and 0.34 (0.17–0.67), respectively, among patients with a family history of GC (p < 0.001) and 1.01 (0.91–1.13), 0.95 (0.86–1.04), 0.86 (0.75–0.98), 0.67 (0.56–0.81), 0.56 (0.44–0.71), 0.51 (0.38–0.68), and 0.33 (0.23–0.47), respectively, among patients without a family history of GC (p < 0.001). Conclusion: In patients with and without a family history of GC, young age at H. pylori eradication was significantly associated with a reduced risk of GC, suggesting that the early treatment of H. pylori infection can maximize GC prevention.
Phenotypic Plasticity in Circulating Tumor Cells Is Associated with Poor Response to Therapy in Metastatic Breast Cancer Patients
Authors: Cohen Evan N. , Jayachandran Gitanjali , Gao Hui , Peabody Phillip , McBride Heather B. , Alvarez Franklin D. , Kai Megumi , Song Juhee , Shen Yu , Willey Jie S. , Lim Bora , Valero Vicente , Ueno Naoto T. , Reuben James M.
Published: March 2023

Circulating tumor cells (CTCs) are indicators of metastatic spread and progression. In a longitudinal, single-center trial of patients with metastatic breast cancer starting a new line of treatment, a microcavity array was used to enrich CTCs from 184 patients at up to 9 timepoints at 3-month intervals. CTCs were analyzed in parallel samples from the same blood draw by imaging and by gene expression profiling to capture CTC phenotypic plasticity. Enumeration of CTCs by image analysis relying primarily on epithelial markers from samples obtained before therapy or at 3-month follow-up identified the patients at the highest risk of progression. CTC counts decreased with therapy, and progressors had higher CTC counts than non-progressors. CTC count was prognostic primarily at the start of therapy in univariate and multivariate analyses but had less prognostic utility at 6 months to 1 year later. In contrast, gene expression, including both epithelial and mesenchymal markers, identified high-risk patients after 6–9 months of treatment, and progressors had a shift towards mesenchymal CTC gene expression on therapy. Cross-sectional analysis showed higher CTC-related gene expression in progressors 6–15 months after baseline. Furthermore, patients with higher CTC counts and CTC gene expression experienced more progression events. Longitudinal time-dependent multivariate analysis indicated that CTC count, triple-negative status, and CTC expression of FGFR1 significantly correlated with inferior progression-free survival while CTC count and triple-negative status correlated with inferior overall survival. This highlights the utility of protein-agnostic CTC enrichment and multimodality analysis to capture the heterogeneity of CTCs.
Cancer-Associated Fibroblast: Role in Prostate Cancer Progression to Metastatic Disease and Therapeutic Resistance
Authors: Bedeschi Martina , Marino Noemi , Cavassi Elena , Piccinini Filippo , Tesei Anna
Published: March 2023

Prostate cancer (PCa) is one of the most common cancers in European males. Although therapeutic approaches have changed in recent years, and several new drugs have been approved by the Food and Drug Administration (FDA), androgen deprivation therapy (ADT) remains the standard of care. Currently, PCa represents a clinical and economic burden due to the development of resistance to ADT, paving the way to cancer progression, metastasis, and to long-term side effects induced by ADT and radio-chemotherapeutic regimens. In light of this, a growing number of studies are focusing on the tumor microenvironment (TME) because of its role in supporting tumor growth. Cancer-associated fibroblasts (CAFs) have a central function in the TME because they communicate with prostate cancer cells, altering their metabolism and sensitivity to drugs; hence, targeted therapy against the TME, and, in particular, CAFs, could represent an alternative therapeutic approach to defeat therapy resistance in PCa. In this review, we focus on different CAF origins, subsets, and functions to highlight their potential in future therapeutic strategies for prostate cancer.
Perfusion Air Culture of Precision-Cut Tumor Slices: An Ex Vivo System to Evaluate Individual Drug Response under Controlled Culture Conditions
Authors: Dong Meng , Böpple Kathrin , Thiel Julia , Winkler Bernd , Liang Chunguang , Schueler Julia , Davies Emma J. , Barry Simon T. , Metsalu Tauno , Mürdter Thomas E. , Sauer Georg , Ott German , Schwab Matthias , Aulitzky Walter E.
Published: March 2023

Precision-cut tumor slices (PCTS) maintain tissue heterogeneity concerning different cell types and preserve the tumor microenvironment (TME). Typically, PCTS are cultured statically on a filter support at an air–liquid interface, which gives rise to intra-slice gradients during culture. To overcome this problem, we developed a perfusion air culture (PAC) system that can provide a continuous and controlled oxygen medium, and drug supply. This makes it an adaptable ex vivo system for evaluating drug responses in a tissue-specific microenvironment. PCTS from mouse xenografts (MCF-7, H1437) and primary human ovarian tumors (primary OV) cultured in the PAC system maintained the morphology, proliferation, and TME for more than 7 days, and no intra-slice gradients were observed. Cultured PCTS were analyzed for DNA damage, apoptosis, and transcriptional biomarkers for the cellular stress response. For the primary OV slices, cisplatin treatment induced a diverse increase in the cleavage of caspase-3 and PD-L1 expression, indicating a heterogeneous response to drug treatment between patients. Immune cells were preserved throughout the culturing period, indicating that immune therapy can be analyzed. The novel PAC system is suitable for assessing individual drug responses and can thus be used as a preclinical model to predict in vivo therapy responses.
Targeting Autophagy Using Long Non-Coding RNAs (LncRNAs): New Landscapes in the Arena of Cancer Therapeutics
Authors: Kumar Aviral , Girisa Sosmitha , Alqahtani Mohammed S. , Abbas Mohamed , Hegde Mangala , Sethi Gautam , Kunnumakkara Ajaikumar B.
Published: March 2023

Cancer has become a global health hazard accounting for 10 million deaths in the year 2020. Although different treatment approaches have increased patient overall survival, treatment for advanced stages still suffers from poor clinical outcomes. The ever-increasing prevalence of cancer has led to a reanalysis of cellular and molecular events in the hope to identify and develop a cure for this multigenic disease. Autophagy, an evolutionary conserved catabolic process, eliminates protein aggregates and damaged organelles to maintain cellular homeostasis. Accumulating evidence has implicated the deregulation of autophagic pathways to be associated with various hallmarks of cancer. Autophagy exhibits both tumor-promoting and suppressive effects based on the tumor stage and grades. Majorly, it maintains the cancer microenvironment homeostasis by promoting viability and nutrient recycling under hypoxic and nutrient-deprived conditions. Recent investigations have discovered long non-coding RNAs (lncRNAs) as master regulators of autophagic gene expression. lncRNAs, by sequestering autophagy-related microRNAs, have been known to modulate various hallmarks of cancer, such as survival, proliferation, EMT, migration, invasion, angiogenesis, and metastasis. This review delineates the mechanistic role of various lncRNAs involved in modulating autophagy and their related proteins in different cancers.
Novel Nitrate Ion-Selective Microsensor Fabricated by Means of Direct Ink Writing
Authors: Paré Franc , Visús Aida , Gabriel Gemma , Baeza Mireia
Published: March 2023

In this work, the stability, electrical conductivity, and versatility of graphite-based inks were taken advantage of to fabricate a nitrate potentiometric sensor. One other key property that was exploited for the design of an ion-selective electrode was the hydrophobicity of graphite. This prevented the formation of a water layer between the solid contact and the polymeric selective membrane. Moreover, given the use of printing technologies for electrode fabrication, it was possible to easily miniaturize the sensors and achieve lower fabrication costs. In this article, a printed sensor, composed of a graphite working electrode and a Ag/AgCl reference electrode, is presented and thoroughly characterized. The working electrode was modified with a well-known PVC-ionophore membrane, and the reference electrode was protected with a PVB-NaCl saturated membrane. It showed almost-Nernstian sensitivity of −(55.4 ± 0.7) mV/dec to NO3−, stability of up to 25 days of operation, limit of detection of 0.204 ± 0.009 mM, and repeatability of 99.02 % (N = 3). Coupled with its high selectivity compared with other anions, this low-cost, mass-producible sensor is a great alternative for environmental and industrial applications.
Aggregation-Induced Emission-Active Iridium(III) Complexes for Sensing Picric Acid in Water
Authors: He Ping , Chen Yan , Li Xiao-Na , Yan Ying-Ying , Liu Chun
Published: March 2023

Herein, two new iridium(III) complexes, namely Ir2 and Ir3, with a phenyl or triphenylamine (TPA) moiety at the 4-position of the phenyl ring at 2-phenylbenzothiazole, have been synthesized, and their emission properties have been studied systematically compared with the non-substituted complex Ir1. These three complexes exhibit aggregation-induced emission (AIE) in H2O/CH3CN. The TPA-substituted complex Ir3 shows the highest AIE activity. All complexes can be used as sensors to detect picric acid (PA) in water. The Stern–Volmer constant (KSV) of Ir3 for the detection of PA was determined to be 1.96 × 106 M−1, with a low limit of detection of 2.52 nM. Proton nuclear magnetic resonance spectra, high-resolution mass spectrometry analysis, and density function theory calculations confirm that the emission quenching mechanism of Ir3 is caused by photo-induced electron transfer. Furthermore, the efficient detection of PA in natural water proves that Ir1–Ir3 can be used as promising sensors in the natural environment. These results suggest that the AIE-active iridium(III) complexes can be used to detect PA under environment-friendly conditions.