Initial Progress Research Articles

Quantum Dots-Based Protocols for the Detection of RNAs.

RNA (ribonucleic acid) plays a crucial role in various cellular processes and is involved in the development and progression of several diseases. RNA molecules have gained considerable attention as potential biomarkers for various ailments, as they reflect the activity of genes in a particular cell or tissue. By measuring the levels of specific RNA molecules, such as messenger RNA (mRNA), noncoding RNAs, including microRNAs (miRNAs), and long noncoding RNAs (lncRNAs), researchers can infer the expression patterns of genes associated with a particular disease. Aberrant expression of specific miRNAs or lncRNAs has been associated with conditions such as cancer, cardiovascular diseases, neurodegenerative disorders, and more. Detection and quantification of these RNAs in biological samples, such as blood or tissue, can provide valuable diagnostic or prognostic information. Yet their analysis is a challenging endeavor due to their length, sequence similarity across family members, sensitivity to disintegration, and low quantity in total samples. New advances in nanophotonics have provided novel options for fabrication of quantum dots (QDs)-based biosensing devices capable of detecting a variety of disease-specific RNAs. Thus, we proposed and designed a nanophotonic method employing oligonucleotide-conjugated quantum dot nanoconjugates for the rapid and accurate detection of RNAs. Despite the abundance of other molecules in the sample, the approach delivers highly selective, precise identification of the target RNAs. The data also indicated the method's great practicality and simplicity in determining RNAs selectively. Overall, the approach enables the evaluation of RNA expression in relation to the initial onset and progression of a human health disorder.

Current concepts of the crosstalk between lncRNA and E2F1: shedding light on the cancer therapy.

Long noncoding RNAs (lncRNAs) constitute a distinctive subset of RNA molecules with limited protein-coding potential, which exert crucial impacts on various biological activities. In the context of cancer, dysregulated lncRNAs function as essential regulators that affect tumor initiation and malignant progression. These lncRNAs serve as competitive endogenous RNAs (ceRNAs) through sponging microRNAs and regulating the expression of targeted genes. Moreover, they also directly bind to RNA-binding proteins, which can be integrated into a complex mechanistic network. E2F1, an extensively studied transcription factor, mediates multiple malignant behaviors by regulating cell cycle progression, tumor metastasis, and therapeutic response. Emerging evidence suggests that lncRNAs play a pivotal role in regulating the E2F1 pathway. This review aims to elucidate the intricate gene regulatory programs between lncRNAs and E2F1 in cancer progression. We elaborate on distinct mechanistic networks involved in cancer progression, emphasizing the potential of the lncRNAs/E2F1 axes as promising targets for cancer therapy. Additionally, we provide novel perspectives on current evidence, limitations, and future directions for targeting lncRNAs in human cancers. Fully deciphering the intricate network of lncRNA/E2F1-mediated regulatory mechanisms in cancer could facilitate the translation of current findings into clinical course, such efforts ultimately significantly improve the clinical prognosis of cancer patients.

Bromodomain Proteins Epigenetically Regulate the Mitotically Associated lncRNA MANCR in Triple Negative Breast Cancer Cells.

Long non-coding RNA (lncRNA)-mediated control of gene expression contributes to regulation of biological processes that include proliferation and phenotype, as well as compromised expression of genes that are functionally linked to cancer initiation and tumor progression. lncRNAs have emerged as novel targets and biomarkers in breast cancer. We have shown that mitotically associated lncRNA MANCR is expressed in triple-negative breast cancer (TNBC) cells and that it serves a critical role in promoting genome stability and survival in aggressive breast cancer cells. Using an siRNA strategy, we selectively depleted BRD2, BRD3, and BRD4, singly and in combination, to establish which bromodomain proteins regulate MANCR expression in TNBC cells. Our findings were confirmed by using in situ hybridization combined with immunofluorescence analysis that revealed BRD4, either alone or with BRD2 and BRD3, can support MANCR regulation of TNBC cells. Here we provide evidence for MANCR-responsive epigenetic control of super enhancers by histone modifications that are required for gene transcription to support cell survival and expression of the epithelial tumor phenotype in triple negative breast cancer cells.

Patterns of early literacy and word reading skill development across the first 6 months of school and reading instruction.

This study described the growth trajectories of 105 children (n = 55 boys) who had just started primary school in New Zealand (NZ). Children were assessed every fourth school week around 1.5 months after starting school, for five sessions on Dynamic Indicators of Basic Early Literacy Skills first sound fluency (FSF), AIMSweb letter sound fluency (LSF), and a newly created NZ word identification fluency (NZWIF-Y1), designed for alignment with beginning reading instruction in NZ. In addition to progress monitoring tasks, children were assessed at school entry and after progress monitoring on literacy-related criterion measures. All three progress monitoring measures were sensitive to growth over the children's first 6 months of school. Cross-sectional time-series analyses indicated that within-child increases in FSF and LSF were associated with increases in NZWIF-Y1, although FSF did not add unique variance when both FSF and LSF were entered as predictors. Furthermore, growth mixture modeling indicated three latent growth trajectories for each indicator (FSF, LSF, NZWIF-Y1, respectively): Class 1-high initial scores and strong growth over time (72.09%, 55.87%, 22.81%); Class 2-lower initial scores and moderate growth over time (19.18%, 29.12%, 54.30%); and Class 3-low initial scores and limited progress over time (8.73%, 15.00%, 22.89%). Criterion measures assessed prior and after progress monitoring were typically associated with latent class membership. Results suggest relative growth in performance on repeated assessment of early literacy and word reading skills in beginning reading instruction distinguishes groups of students with differential skill acquisition. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Impact of the Ventricle Size on Alzheimer's Disease Progression: A Retrospective Longitudinal Study.

Ventricle enlargement has been implicated in the pathophysiology of Alzheimer's disease (AD). We studied the relationship between ventricular size and cognitive function in patients with AD. We focused on the effect of the initial ventricle size on the rate of cognitive decline in patients with AD. A retrospective analysis of probable clinical AD participants with more than 2 magnetic resonance imaging images was performed. To measure ventricle size, we used visual rating scales of (1) Cardiovascular Health Study (CHS) score and (2) conventional linear measurement method. Increased clinical dementia rating (CDR) was correlated with a decreased Mini-Mental Status Examination (MMSE) score, and increased medial temporal lobe atrophy (MTLA) and global ventricle size (p<0.001, p<0.001, p=0.021, respectively). There was a significant correlation between the change in cognitive function in the group (70%-100%ile) with a large initial ventricle size (p=0.021 for ΔCDR, p=0.01 for ΔMMSE), while the median ventricle size (30%-70%ile) showed correlation with other brain structural changes (MTLA, frontal atrophy [FA], and white matter) (p=0.036 for initial MTLA, p=0.034 for FA). In this study, the initial ventricle size may be a potential new imaging biomarker for initial cognitive function and clinical progression in AD. We found a relationship between the initial ventricle size and initial AD-related brain structural biomarkers.

Fragment-based drug discovery campaigns guided by native mass spectrometry.

Native mass spectrometry (nMS) is well established as a biophysical technique for characterising biomolecules and their interactions with endogenous or investigational small molecule ligands. The high sensitivity mass measurements make nMS particularly well suited for applications in fragment-based drug discovery (FBDD) screening campaigns where the detection of weakly binding ligands to a target biomolecule is crucial. We first reviewed the contributions of nMS to guiding FBDD hit identification in 2013, providing a comprehensive perspective on the early adoption of nMS for fragment screening. Here we update this initial progress with a focus on contributions of nMS that have guided FBDD for the period 2014 until end of 2023. We highlight the development of nMS adoption in FBDD in the context of other biophysical fragment screening techniques. We also discuss the roadmap for increased adoption of nMS for fragment screening beyond soluble proteins, including for guiding the discovery of fragments supporting advances in PROTAC discovery, RNA-binding small molecules and covalent therapeutic drug discovery.

Challenges to the development of taxation policies for sugar-sweetened beverages in Colombia

Frequent consumption of sugar sweetened beverages (SSB) is related to the risks of developing overweight, obesity, cavities, diabetes and other diseases. Policies to significantly increase taxes on SSB have proven...

Integrating diversity into the medical curriculum

In the field of medical education, diversity refers to the presence and representation of persons from a diversified range of personal backgrounds, experiences, and characteristics across the student community, faculty members, and employees in the institution. The scope of diversity in medical education is immense and it plays a vital role in creating an effective learning environment. Once students are exposed to a group of diverse students and patients during their undergraduate training, there is a significant improvement in cultural competence, which becomes crucial in our mission to deliver patient-centered care. Considering the merits of diversity in the medical curriculum for medical students, there is an indispensable need to take specific measures to ensure that diversity is integrated in the curriculum, as it will also ensure the delivery of equitable and culturally competent medical care. As important is to ensure the integration of diversity into medical curriculum, equal importance has to be given to the measurement of various initiatives that have been taken to promote diversity in medical education. In conclusion, diversity in medical education is the need of the hour to create a fruitful learning environment for medical students. This calls for the need to take measures for the integration of diversity into the medical curriculum and subsequently identify strategies and indicators to measure and monitor the progress of diversity initiatives in medical institutions.

Study on effects of 40 Hz light flicker stimulation on spatial working memory in rats and its neural mechanism

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment, with the predominant clinical diagnosis of spatial working memory (SWM) deficiency, which seriously affects the physical and mental health of patients. However, the current pharmacological therapies have unsatisfactory cure rates and other problems, so non-pharmacological physical therapies have gradually received widespread attention. Recently, a novel treatment using 40 Hz light flicker stimulation (40 Hz-LFS) to rescue the cognitive function of model animals with AD has made initial progress, but the neurophysiological mechanism remains unclear. Therefore, this paper will explore the potential neural mechanisms underlying the modulation of SWM by 40 Hz-LFS based on cross-frequency coupling (CFC). Ten adult Wistar rats were first subjected to acute LFS at frequencies of 20, 40, and 60 Hz. The entrainment effect of LFS with different frequency on neural oscillations in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was analyzed. The results showed that acute 40 Hz-LFS was able to develop strong entrainment and significantly modulate the oscillation power of the low-frequency gamma (lγ) rhythms. The rats were then randomly divided into experimental and control groups of 5 rats each for a long-term 40 Hz-LFS (7 d). Their SWM function was assessed by a T-maze task, and the CFC changes in the HPC-mPFC circuit were analyzed by phase-amplitude coupling (PAC). The results showed that the behavioral performance of the experimental group was improved and the PAC of θ-lγ rhythm was enhanced, and the difference was statistically significant. The results of this paper suggested that the long-term 40 Hz-LFS effectively improved SWM function in rats, which may be attributed to its enhanced communication of different rhythmic oscillations in the relevant neural circuits. It is expected that the study in this paper will build a foundation for further research on the mechanism of 40 Hz-LFS to improve cognitive function and promote its clinical application in the future.

Baseline GABA+ levels in areas associated with sensorimotor control predict initial and long-term motor learning progress.

Synaptic plasticity relies on the balance between excitation and inhibition in the brain. As the primary inhibitory and excitatory neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate (Glu), play critical roles in synaptic plasticity and learning. However, the role of these neurometabolites in motor learning is still unclear. Furthermore, it remains to be investigated which neurometabolite levels from the regions composing the sensorimotor network predict future learning outcome. Here, we studied the role of baseline neurometabolite levels in four task-related brain areas during different stages of motor skill learning under two different feedback (FB) conditions. Fifty-one healthy participants were trained on a bimanual motor task over 5 days while receiving either concurrent augmented visual FB (CA-VFB group, N = 25) or terminal intrinsic visual FB (TA-VFB group, N = 26) of their performance. Additionally, MRS-measured baseline GABA+ (GABA + macromolecules) and Glx (Glu + glutamine) levels were measured in the primary motor cortex (M1), primary somatosensory cortex (S1), dorsolateral prefrontal cortex (DLPFC), and medial temporal cortex (MT/V5). Behaviorally, our results revealed that the CA-VFB group outperformed the TA-VFB group during task performance in the presence of augmented VFB, while the TA-VFB group outperformed the CA-VFB group in the absence of augmented FB. Moreover, baseline M1 GABA+ levels positively predicted and DLPFC GABA+ levels negatively predicted both initial and long-term motor learning progress in the TA-VFB group. In contrast, baseline S1 GABA+ levels positively predicted initial and long-term motor learning progress in the CA-VFB group. Glx levels did not predict learning progress. Together, these findings suggest that baseline GABA+ levels predict motor learning capability, yet depending on the FB training conditions afforded to the participants.

Knowledge graph construction and visualization analysis of coal mine accident safety management research based on CiteSpace and VOSviewer

Although the coal mining industry has implemented mechanization and automation, frequent coal mine accidents still occur, making coal mine safety a primary concern. To gain a comprehensive understanding of global progress in preventing coal mine accidents and managing safety, we utilized the Web of Science database (WOS) as our sample source. With the support of CiteSpace and VOSviewer software, we constructed a knowledge graph depicting publication numbers, research institutions, and keyword clustering to visually analyze coal mine accident prevention and safety management. Our research reveals that this field has undergone three stages of development: initial growth, steady progress, and rapid advancement. Particularly noteworthy is the current golden age of rapid development from 2018 to 2023 which has garnered significant attention from researchers. In terms of author collaboration networks, notable contributors with high publication rates and citation counts include Wu Qiang, Liu Quanlong, et al. Regarding institutional cooperation networks, major research institutions such as China University of Mining &amp; Technology, Shandong University of Science &amp; Technology, and Anhui University are actively engaged in important scientific research related to coal mining. Through keyword clustering analysis based on relevant literature review, it is evident that research on coal mine safety management primarily focuses on high-frequency keywords such as "coal and gas outburst","risk assessment" and "coal miners" By extracting the top nine emergent keywords with high-intensity levels and arranging them chronologically according to their emergence year, the evolution pattern over time was obtained for emergent words. Furthermore, it was observed that emerging keywords like "China", "subsidence" and "workers" have also gained increasing attention during this period.

Radiotherapy to reinvigorate immunotherapy activity after acquired resistance in metastatic non-small-cell lung cancer: A pooled analysis of two institutions prospective phase II single arm trials

AimThe current work aimed to investigate the clinical benefit of radiotherapy in patients with metastatic non-small cell lung cancer (NSCLC) developing acquired resistance to immune checkpoint inhibitors. MethodWe report on a pooled, two-institution, phase II single-arm prospective cohort study. The study included patients with stage IV NSCLC who showed progression of one or more measurable lesions under anti-PD-(L)1 inhibition alone, after initially having achieved at least stable disease. Hypofractionated radiotherapy (hRT) of one to four metastases was performed, while one or more lesions were kept untreated. Following hRT, treatment with immune checkpoint inhibitors was continued unchanged until further evidence of tumor progression or unacceptable toxicity. Primary endpoint of the pooled analysis was progression-free survival (PFS), secondary endpoints included overall survival (OS) and toxicity. ResultsA total of 48 patients were enrolled: mean age was 67.1 ± 9.3 years, 50 % were male and 72.9 % were PD-L1 positive. Immunotherapy was in 95.8 % of patients the first or second line therapy at time of enrollment. hRT was performed to one (93.8 % of cases) or more lesions (median total dose: 27.5 Gy, median 6.5 Gy/fraction). Forty-five patients (93.8 %) were able to continue immunotherapy for a median of 6.2 months following hRT. Median PFS was 4.4 months, with 62.5 % disease control at three months and 37.5 % at six months. Median OS was 14.9 months. Severe adverse events (grade ≥ 2) were reported in 12 cases (25 %), of which none were radiotherapy-related and four were immunotherapy-related. Salvage therapy consisted of chemotherapy (48.8 %) or repeated irradiation (21.9 %). No further tumor treatment was performed in 29.3 % of patients. ConclusionsThe current pooled analysis is a prospective evaluation of the role of radiation therapy for metastatic NSCLC in the setting of newly acquired immunotherapy resistance. Hypofractionated radiotherapy can support the outcome of immune checkpoint inhibitors and thus allow continuation of treatment for a relevant amount of time despite initial tumor progression.

GIS-driven Hydro Energy Potential Estimation for Technoeconomic Assessment of Hydro Power Plant in Bawean, Gresik

This study aims to assess the spatial distribution of hydropower capacity on Bawean Island using a Geographic Information System (GIS). The objective of this study is to provide a valuable contribution to the progress of sustainable energy transition initiatives in Indonesia. The primary objective of the hydropower map is to enhance the process of strategic planning and implementation of hydropower infrastructure, with a particular emphasis on supplying electricity to rural regions. The essential components required for the successful implementation of hydropower are the head, which represents the vertical distance between the water source and the water outflow, which refers to the rate at which water is discharged from the system. Bawean Island, located in the eastern region of Java, possesses a unique topographical structure distinguished by an abundance of rivers, making it a promising site for the establishment of hydropower infrastructure. The utilization of ArcGIS was applied for the aim of hydropower mapping. The estimation of water discharge was conducted using the Soil Conservation Service-Curve Number (SCS-CN) approach. The current investigation utilized the Multi-Criteria Decision Analysis (MCDA) framework, which incorporated the Analytical Hierarchy Process (AHP) and the Technique for Order Preference by Similarity to the Ideal Solution (TOPSIS) to ascertain the most advantageous choice of hydropower plant types for deployment in the Bawean region. The classifications comprise pico-hydro, micro-hydro, mini-hydro, and large-scale hydropower installations.The Multi-Criteria Decision Analysis (MCDA) framework incorporates various criteria, including cost, policy, social concerns, technology assistance, integration, and natural catastrophe considerations. The results indicate that the hydropower potential on Bawean Island peaks in January, coinciding with the rainy season, while it is at its lowest in August, corresponding to the dry season. Moreover, the spectrum of hydropower installations suitable for Bawean Island includes pico-hydro systems, which have a power generation capacity of up to 5 kW. Additionally, mini-hydro plants are categorized into two classes: class A, with a power generation capacity ranging from 5 to 100 kW, and class B, with a power generation capacity ranging from 100 to 200 kW. The utilization of Multi-criterion Decision Analysis (MCDA) reveals the results of the techno-economic assessment, emphasizing the importance of cost, social factors, and policy as the key criterion for decision-making. The factors mentioned above are allocated weights of 0.44, 0.17, and 0.17, correspondingly. Pico-hydro is a suggested category of hydropower plants that are being considered for the development of hydropower infrastructure in the Bawean region.

Attractiveness measurement of bai kuyao ethnic tourism attractors from the perspective of tourist perception

Named after the men donning white pants, Bai kuyao, a subgroup of the Yao ethnic community, preserves a substantial portion of its original ethnic heritage. The utilization of these ethnic traditions within the realm of tourism development has emerged as a pivotal concern. This study, initiated from the vantage point of tourists' perceptions, established an evaluative framework for assessing the attractiveness of Bai kuyao ethnic tourism. The framework was constructed through expert interviews and literature analysis. Utilizing the fuzzy analytic hierarchy process and IPA analysis techniques, the ethnic tourism appeal of Bai kuyao was quantified. The analysis of data disclosed that Bai kuyao's clothing culture, folk traditions, architectural heritage, and experiential activities hold considerable allure for tourists. However, tourists' overall satisfaction with their tourism experiences remains relatively low. The findings of this research offer valuable insights, serving as recommendations for the development and sustainable progression of tourism initiatives in Bai kuyao.

Enrollment and Scientific Progress of the Multisite SuperAging Research Initiative

AbstractBackgroundThe SuperAging Research Initiative is a multisite consortium focused on identifying factors promoting extraordinary cognitive aging. The designation of SuperAger is reserved for individuals age 80+ who have episodic memory capacity that would be considered at least average for those 2‐3 decades younger. The presence of such outliers raises questions of fundamental importance to the neurobiology of brain aging, resilience, resistance, and avoidance of cognitive decline caused by Alzheimer’s disease. The original study of SuperAgers emerged at Northwestern and helped establish the phenotype. The SuperAging Research Initiative was established in 2021 and is focused on increasing minority representation and expanding deep phenotyping of this unique population.MethodsHarmonized data collection has been initiated across the five sites including behavioral, health, biologic, genetic, environmental, socioeconomic, psychosocial, neuroanatomic, and neuropathologic factors. Here we summarize the initial recruitment progress and baseline characteristics of the current cohort.ResultsWe will present the organizational structure, progress, and baseline characteristics of the cohort to date. The SuperAging Research Initiative includes three Cores (Administrative/Biostatistics, Clinical/Imaging, and Biospecimen/Neuropathology) and two Research Projects. Enrollment (target, n = 500) has commenced across four U.S. Sites located in Illinois, Wisconsin, Michigan, and Georgia, and a Canadian Site in Southwest Ontario, with a focus on enrollment of Black SuperAgers and Cognitively Average Elderly Controls with similar demographics. Project 1 uses state‐of‐the‐art wearable technology to obtain quantitative measurements of daily life including, sleep, physical activity, autonomic responsivity, and social engagement to determine whether SuperAgers have relatively preserved physiologic and behavioral ‘complexity’ compared to Controls. Project 2 focuses on transcriptomic, genetic, and protein profiling to examine central and peripheral immune and inflammatory system parameters of SuperAgers.ConclusionsBy identifying factors contributing to superior memory performance in old age, outcomes may help isolate modifiable factors that promote healthspan and perhaps also prevent age‐related brain diseases such as Alzheimer’s disease.

CKD-Associated Pruritus and Clinical Outcomes in Nondialysis CKD

Itching is a frequent symptom experienced by people with chronic kidney disease (CKD). We investigated the associations of CKD-associated pruritus (CKD-aP) with clinical outcomes. This was a longitudinal cohort study. Patients from Brazil, France, and the United States enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) from 2013 to 2021, an international prospective cohort study of adults with nondialysis dependent CKD, and an estimated glomerular filtration rate (eGFR) of<60 mL/min/1.73 m2 were included. CKD-aP was self-reported by response to the question: "During the past 4 weeks, to what extent were you bothered by itchy skin?" The outcomes were as follows: CKD progression, kidney replacement therapy (KRT) initiation, mortality, hospitalization, cardiovascular events, infection events. Associations with time-to-event outcomes were investigated using Cox proportional hazards models adjusted for potential confounders. There were 4,410 patients from 91 clinics with a median age of 69 years and a median eGFR at patient questionnaire completion of 29 (21-38) mL/min/1.73 m2. The proportion of patients not at all, somewhat, moderately, very much, and extremely bothered by itchy skin was 49%, 27%, 13%, 7%, and 3%, respectively. Patients with more advanced stages of CKD, older age, and greater comorbidities reported to be more likely bothered by itchy skin. Among patients at least moderately bothered, 23% were prescribed at least 1 pharmacotherapy (35% in the United States, 19% in France, 4% in Brazil), including antihistamine (10%), gabapentin (6%), topical corticosteroids (4%), pregabalin (3%), or sedating antihistamine (3%). The HR (95% CI) for patients extremely (vs not at all) bothered was 1.74 (1.11-2.73) for all-cause mortality, 1.56 (1.11-2.18) for all-cause hospitalization, and 1.84 (1.22-2.75) for cardiovascular events. As CKD-aP severity increased, patients also had higher rates of infection events (P= 0.04); CKD-aP severity was not associated with KRT initiation (P= 0.20) or CKD progression (P= 0.87). The limitations were 25% nonresponse rate, recall bias, and residual confounding factors. These results demonstrate a strong association between severe itch and clinical outcomes, providing the nephrology community new insights into the possible adverse consequences of CKD-aP in individuals with nondialysis CKD, and warrant further exploration. Chronic kidney disease-associated pruritus (CKD-aP) is a common disturbing symptom of chronic kidney disease (CKD). This article analyzes longitudinal data from the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) to describe prevalence of CKD-aP in 4,410 individuals with nondialysis CKD, and its association with clinical outcomes. We found that 51% of the surveyed population were bothered by pruritus. CKD-aP was more prevalent in those with more advanced stages of CKD, older age, and with more comorbid conditions. Compared to those not at all bothered by pruritus, those who were extremely bothered had a higher risk of all-cause mortality, hospitalizations, and cardiovascular events. Severity of CKD-aP was not associated with CKD progression or initiation of kidney replacement therapy.

Measuring Residents’ and Visitors’ Satisfaction with Sustainable Tourism—The Case of “Rusanda” Nature Park, Vojvodina Province

The Nature Park “Rusanda” (NPR) is a designated area under the second category of national protection. Situated in the Vojvodina Province, in the northern region of Serbia, its accessibility to a substantial number of international visitors is enhanced by its proximity to Romania and Hungary. Lake Rusanda and the salt marsh habitats render this region a sanctuary for rare avian species. This ecological significance has led to the NPR being designated as an IBA area—an Important Bird and Biodiversity Area by Birdlife. Beyond its natural attributes, the NPR stands out for its diverse cultural heritage, stemming from the local population residing in its immediate vicinity. A notable characteristic is the diverse ethnic makeup, contributing to a wide array of cultures, traditional attire, original folk music, customs, and cuisine, collectively forming a distinctive cultural heritage unique to this part of Vojvodina. To assess the status of sustainable tourism and its impact on the satisfaction of both residents and tourists within the NPR, the Prism of Sustainability model (PoS) is employed. In the quantitative approach, a survey questionnaire was utilized as a research tool, with a total of 840 participants included through a randomized sampling technique. Regression analysis of the study’s results indicates that sustainable tourism exerts a significant influence on the contentment of local people and tourists in the NPR. Given the presence of diverse ecological and societal elements, in addition to the existence of rare flora and fauna species, the central thrust in tourism development should focus on preserving and involving local residents in the planning and progress of tourism initiatives. The primary types of tourism that are poised for success in the NPR encompass ecotourism, wellness and spa tourism, nature-based tourism, birdwatching, scientific research tourism, and excursions.

Perspectives on Digital Transformation Initiatives in the Mechanical Engineering Industry

Companies from the mechanical engineering industry are eager to embrace new technologies in their pursuit of a competitive advantage. However, the complete digitalization of the sector encounters limitations, as certain aspects necessitate human supervision or manual labor. This is where the concepts of Industry 4.0, Industry 5.0, and digital transformation become relevant. The aim of the research presented in this paper was to gather and extract valuable insights and lessons from the experiences of German companies in the plastic extrusion machinery sector with digital transformation (DT). Qualitative interpretative research was used, using in-depth expert interviews with C-level executives. We organized the findings into three categories: (i) DT communication initiatives, including the elimination of paper, CRM solutions, messenger services, home office, and online procurement platforms; (ii) departments and areas most involved, including accounting and procurement, sales and production, and construction; and (iii) cost–benefit perception, including positive assessment, long-term impacts, and variation from company to company. The results provide valuable insights into the progress of DT initiatives in companies operating in the pipe extrusion sector in Germany. Additionally, several DT misconceptions were identified, thereby enriching the DT misconceptions framework that has been intensely discussed in the DT literature.

IMMU-24. SALVAGE IMMUNOTHERAPIES FOR REPLICATION REPAIR DEFICIENT (RRD) HIGH-GRADE GLIOMA FAILING ANTI-PD1 MONOTHERAPY: A REPORT FROM THE INTERNATIONAL RRD CONSORTIUM

Abstract BACKGROUND Initial response to immune checkpoint inhibition (ICI) for DNA replication-repair deficient high-grade glioma (RRD-HGG) is encouraging. However, clinical/biologic implications of immune-directed approaches after failing ICI-monotherapy remain unknown. METHODS We performed an international study of patients managed using central review/treatment recommendations (2015-2021). Salvage after anti-PD1 failure included re-irradiation where feasible, and addition of anti-CTLA4 (ipilimumab), or a MEK-inhibitor (MEKi). Outcomes included radiological response (iRANO), toxicity, second progression-free (PFS2) and overall survival (OS2). Companion biomarkers were performed centrally. RESULTS Twenty among 75 patients treated on anti-PD1 monotherapy are progression-free at a median follow-up of 44.6-months. For 55 patients with relapsed/progressive tumors, continuation of ICI (n=38) resulted in median OS2 of 11.6-months (51% alive) versus 1.2-months when ICI was discontinued (n=17; no survivors, p&amp;lt; 0.001). Addition of ipilimumab (n=24) resulted in response/stable disease in 75% with median OS2 of 12.1-months. High autoimmune toxicities (54%) were observed, particularly in constitutional mismatch-repair deficiency patients. The addition of MEKi led to response in 3/5 patients with prolonged survival. The addition of re-irradiation improved median OS2, especially in tumors with lower mutation burden (p=0.002), and those who received ipilimumab (median OS2=33-months). Several biological insights were gained. Increased CTLA4 expression explained responses to ipilimumab. Re-irradiation responses were attributed to the absence of radio-resistant indel signature (ID8). Early radiological ‘flare’ was observed in 33% on combined immunotherapy and re-radiation. MEKi responses were associated with reinvigoration of peripheral immune response. Finally, delayed, sustained responses were observed in ultra-hypermutant RRD-HGG exhibiting changes in somatic mutational spectra. CONCLUSION These data suggest that the continuous mutagenesis renders hypermutant RRD-HGG susceptible to checkpoint inhibitors beyond initial progression. The combination with re-irradiation and additional immune/targeted agents can maximize survival in these children and young adults. Future research should focus on biology-driven rational immunotherapy combinations that also result in lower toxicity to maximize patient benefit.

NIMG-29. ADVANCED MRI BIOMARKERS PREDICT EARLY RESPONSE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA

Abstract BACKGROUND Tumor-treating fields (TTFields) is a novel US FDA-approved antimitotic treatment modality for patients with newly diagnosed and recurrent glioblastoma, shown to improve both OS and PFS (Stupp et al 2015). Yet, how to best monitor response to TTfields remains unclear. Conventional (anatomic) MRI is unreliable, often showing initial early radiographic progression followed by tumor regression and clinical benefit, thereby delaying confirmation of response. To address this limitation, we evaluate the utility of quantitative (physiologic) MRI biomarkers. METHODS Patients with newly diagnosed or recurrent IDH wildtype glioblastoma who underwent MRI with DSC-MRI perfusion imaging at 1-2, 3-4 and 5-6 months after TTField treatment were retrospectively identified for this study. Delta T1 (dT1) images were created from standardized (calibrated) pre- and post-contrast T1-weighted images, from which an enhancing lesion volume was objectively determined. Standardized and leakage-corrected relative cerebral blood volume (sRCBV) images were created from the DSC-MRI data. Together, dT1 and sRCBV were used to generate class maps of fractional tumor burden (FTB), which identify highly-vascular and avascular (treatment effect) regions within contrast-enhancement. Kaplan-Meier survival analysis was performed to determine if positive versus negative changes in these metrics, at each time-point relative to pre-treatment values, are predictive of survival. RESULTS 20 patients with newly diagnosed (n=17) or recurrent (n=4) IDH wildtype glioblastoma with a mean TTField compliance of 74.9% were identified. At 1-2 months no metric predicted a survival difference, consistent with the known 4-week delay in tumor stabilization following TTField therapy. At months 3-4 and 5-6 decreasing dT1-determined enhancing volumes showed a survival benefit (p=0.0081, p=0.03). Likewise, a decreasing percentage of highly-vascular tissue, determined from FTB class maps, demonstrated a survival benefit (p=0.0013). CONCLUSIONS Quantitative MRI metrics, including dT1-derived enhancing volumes and FTB/sRCBV-defined regions of high vascularity, demonstrate an ability to provide early indicators of response to TTField treatment.