bluuebunny/crossref_metadata_2025_split huggingface dataset:
Obinutuzumab Pretreatment as a Novel Approach to Mitigate Formation of Anti-Drug Antibodies Against Cergutuzumab Amunaleukin in Patients with Solid Tumors
Authors: Peters Solange , Angevin Eric , Alonso-Gordoa Teresa , Rohrberg Kristoffer , Melero Ignacio , Mellado Begoña , Perez-Gracia Jose-Luis , Tabernero Josep , Adessi Celine , Boetsch Christophe , Watson Carl , Dal Porto Joseph , Dejardin David , Del Nagro Christopher , Nicolini Valeria , Evers Stefan , Klein Christian , Leutgeb Barbara , Pisa Pavel , Rossmann Eva , Saro José , Umana Pablo , Charo Jehad , Teichgräber Volker , Steeghs Neeltje 
Published: February 2024

Abstract

Purpose:
The immunocytokine cergutuzumab amunaleukin (CEA-IL2v) showed manageable safety and favorable pharmacodynamics in phase I/Ib trials in patients with advanced/metastatic carcinoembryonic antigen-positive (CEA+) solid tumors, but this was accompanied by a high incidence of anti-drug antibodies (ADA). We examined B-cell depletion with obinutuzumab as a potential mitigation strategy.

Experimental Design:
Preclinical data comparing B-cell depletion with rituximab versus obinutuzumab are summarized. Substudies of phase I/Ib trials investigated the effect of obinutuzumab pretreatment on ADA development, safety, pharmacodynamics, and antitumor activity of CEA-IL2v ± atezolizumab in patients with advanced/metastatic or unresectable CEA+ solid tumors who had progressed on standard of care.

Results:
Preclinical data showed superior B-cell depletion with obinutuzumab versus rituximab. In clinical studies, patients received CEA-IL2v monotherapy with (n = 16) or without (n = 6) obinutuzumab pretreatment (monotherapy study), or CEA-IL2v + atezolizumab + obinutuzumab pretreatment (n = 5; combination study). In the monotherapy study, after four cycles (every 2 weeks treatment), 0/15 evaluable patients administered obinutuzumab pretreatment had ADAs versus 4/6 patients without obinutuzumab. Obinutuzumab pretreatment with CEA-IL2v monotherapy showed no new safety signals and pharmacodynamic data suggested minimal impact on T cells and natural killer cells. Conversely, increased liver toxicity was observed in the combination study (CEA-IL2v + atezolizumab + obinutuzumab pretreatment).

Conclusions:
These preliminary findings suggest that obinutuzumab pretreatment before CEA-IL2v administration in patients with CEA+ solid tumors may be a feasible and potent ADA mitigation strategy, with an acceptable safety profile, supporting broader investigation of obinutuzumab pretreatment for ADA mitigation in other settings.
Oncogenic GNAS Uses PKA-Dependent and Independent Mechanisms to Induce Cell Proliferation in Human Pancreatic Ductal and Acinar Organoids
Authors: Desai Ridhdhi , Huang Ling , Gonzalez Raul S. , Muthuswamy Senthil K. 
Published: February 2024

Abstract
Ductal and acinar pancreatic organoids are promising models for the study of pancreatic diseases. Genome sequencing studies have revealed that mutations in a G-protein (GNASR201C) are exclusively observed in intraductal papillary mucinous neoplasms (IPMN). The biological mechanisms by which GNASR201C affects the ductal and acinar exocrine pancreas are unclear. Here, we use human stem-cell-derived pancreatic ductal and acinar organoids and demonstrate that GNASR201C was more effective in inducing proliferation in ductal organoids compared with acinar organoids. Surprisingly, GNASR201C-induced cell proliferation was protein kinase A (PKA)-independent in ductal organoids and an immortalized ductal epithelial cell line. Co-expression of oncogenic KRASG12V and GNASR201C retained PKA-independence in ductal organoids to stimulate cell proliferation. Thus, we identify cell lineage-specific roles for PKA signaling in GNASR201C-driven cell proliferation in precancerous lesions and report the development of a human pancreatic ductal organoid model system to investigate mechanisms regulating GNASR201C-induced IPMNs.

Implications:
The study identifies an opportunity to discover a PKA-independent pathway downstream of oncogene GNAS for managing IPMN lesions and their progression to PDAC.
An Endosomal Acid-Regulatory Feedback System Rewires Cytosolic cAMP Metabolism and Drives Tumor Progression
Authors: Prasad Hari , Mandal Susmita , Mathew John Kandam Kulathu , Cherukunnath Aparna , Duddu Atchuta Srinivas , Banerjee Mallar , Ramani Harini , Bhat Ramray , Jolly Mohit Kumar , Visweswariah Sandhya S. 
Published: February 2024

Abstract

Although suppressed cAMP levels have been linked to cancer for nearly five decades, the molecular basis remains uncertain. Here, we identify endosomal pH as a novel regulator of cytosolic cAMP homeostasis and a promoter of transformed phenotypic traits in colorectal cancer. Combining experiments and computational analysis, we show that the Na+/H+ exchanger NHE9 contributes to proton leak and causes luminal alkalinization, which induces resting [Ca2+], and in consequence, represses cAMP levels, creating a feedback loop that echoes nutrient deprivation or hypoxia. Higher NHE9 expression in cancer epithelia is associated with a hybrid epithelial–mesenchymal (E/M) state, poor prognosis, tumor budding, and invasive growth in vitro and in vivo. These findings point to NHE9-mediated cAMP suppression as a pseudostarvation-induced invasion state and potential therapeutic vulnerability in colorectal cancer. Our observations lay the groundwork for future research into the complexities of endosome-driven metabolic reprogramming and phenotype switching and the biology of cancer progression.

Implications:
Endosomal pH regulator NHE9 actively controls cytosolic Ca2+ levels to downregulate the adenylate cyclase–cAMP system, enabling colorectal cancer cells to acquire hybrid E/M characteristics and promoting metastatic progression.
Unilateral Primary Aldosteronism: Long-Term Disease Recurrence After Adrenalectomy
Authors: Tetti Martina , Brüdgam Denise , Burrello Jacopo , Udager Aaron M. , Riester Anna , Knösel Thomas , Beuschlein Felix , Rainey William E. , Reincke Martin , Williams Tracy Ann 
Published: February 2024

BACKGROUND:
Primary aldosteronism (PA) is frequently caused by a unilateral aldosterone-producing adenoma with a PA-driver mutation. Unilateral adrenalectomy has a high probability of short-term biochemical remission, but long-term postsurgical outcomes are relatively undefined. Our objective was to investigate the incidence of long-term recurrence of PA in individuals with postsurgical short-term biochemical remission.

METHODS:
Adrenalectomized patients for unilateral PA were included from a single referral center. Histopathology and outcomes were assessed according to international histopathology of unilateral primary aldosteronism and PASO (Primary Aldosteronism Surgical Outcome) consensuses. Genotyping was performed using CYP11B2 (aldosterone synthase)-guided sequencing.

RESULTS:

Classical adrenal histopathology, exemplified by a solitary aldosterone-producing adenoma, was observed in 78% of 90 adrenals, compared with 22% with nonclassical histopathology. The classical group displayed higher aldosterone-to-renin ratios (
P
=0.013) and lower contralateral ratios (
P
=0.008). Outcome assessments at both short (12 months [7; 12]) and long (89 months [48; 124]) terms were available for 57 patients. At short-term assessment, 53 (93%) displayed complete biochemical success (43 classical and 10 nonclassical), but long-term assessment demonstrated biochemical PA recurrence in 12 (23%) with an overrepresentation of the nonclassical histopathology (6 [60%] of 10 nonclassical histopathology versus 6 [14%] of 43 classical histopathology;
P
=0.005). PA-driver mutations were identified in 97% of 64 aldosterone-producing adenomas; there was no association of the aldosterone-producing adenoma genotype with PA recurrence.

CONCLUSIONS:
A substantial proportion of individuals display postsurgical biochemical recurrence of PA, which is related to the histopathology of the resected adrenal gland. These findings emphasize the role of histopathology and the requirement for continued outcome assessment in the management of surgically treated patients for PA.
Sympathetic and parasympathetic central autonomic networks
Authors: Valenza Gaetano , Ciò Francesco Di , Toschi Nicola , Barbieri Riccardo 
Published: February 2024

Abstract
The central-autonomic network (CAN) comprises brain regions that are functionally linked to the activity of peripheral autonomic nerves. While parasympathetic CAN (i.e., the CAN projecting onto parasympathetic branches) has recently been investigated and is known to be involved in neurological and neuropsychiatric disorders, sympathetic CAN (i.e., the CAN projecting onto sympathetic nerves) has not been fully characterized. Using functional magnetic resonance imaging (fMRI) data from the Human Connectome Project in conjunction with heartbeat dynamics and its orthonormal autoregressive descriptors as a proxy for sympathetic activity estimation, namely, the sympathetic activity index (SAI), we uncover brain regions belonging to the sympathetic CAN at rest. We uncover a widespread CAN comprising both cortical (in all lobes) and subcortical areas, including the cerebellum and brainstem, which is functionally linked to sympathetic activity and overlaps with brain regions driving parasympathetic activity. These findings may constitute fundamental knowledge linking brain and bodily dynamics, including the link between neurological and psychiatric disorders and autonomic dysfunctions.
History of Economics in the Light of Meghnad Desai’s Poverty of Political Economy
Authors: Sinha Ajit 
Published: February 2024

The article discusses some of the major theoretical and practical matters that the discipline of Economics has been grappling with from the times of Adam Smith down to Keynes. The publication of Meghnad Desai’s Poverty of Political Economy turns out to be an occasion or inspiration to revisit these ideas—the article is organised as a review article of the book. JEL Codes: B0, B1, B2, B3
Energy Costs and Greenhouse Gas Emissions of Giant Reed (Arundo donax L.) Production for Use as a Bioenergy Vector
Authors: Santalla Estela , Ressia Juan , Córdoba Verónica , Lázaro Laura 
Published: February 2024

This study estimates the energy costs and greenhouse gas emissions for the production and the processing for thermal use of Giant reed ( Arundo donax L.), a second-generation perennial energy crop. The agronomic study took place in Buenos Aires (Argentina) under humid to subhumid climatic conditions. Rhizomes and in vitro micropropagated plantlets were employed and cultivated under both fertilization and rainfed conditions during 2018–2022. The yield demonstrated a substantial increase from 3.8 t/ha to 23.1 t/ha from implantation to crop setting. Throughout this period, the energy input escalated from 23 to 70 GJ/ha, with the planting phase exhibiting the highest energy intensity. This surge can be attributed to the use of herbicides, accounting for 44.1%–61.3% of the energy consumed. Energy outputs were 17 (±0.19) MJ/kg as the low heating value obtained from the biomass elemental composition. The net energy yield for the 10-year lifecycle resulted in 2851.3 (±20.2) GJ/ha, and the output/input ratio varied from 41 (for pellets) to 126 (for chips). Carbon emissions ranged from 343.9 (for plantlets) to 371.9 (for rhizomes) kg CO2e/ha during the implantation stage, resulting in 208.3, 397.6, and 859.6 kg CO2e/ha for chips, bales, and pellets, respectively. This study reinforced the knowledge about the farming of this energy crop and displayed a promising scenario for the sustainable development of the Arundo donax L. based value chain. JEL Classification Q4, Q43, Q56
Effects of Diclofenac Etalhyaluronate (SI-613/ONO-5704) on Cartilage Degeneration in Arthritic Rats and Inflammatory Cytokine-Stimulated Human Chondrocytes
Authors: Takada Shuhei , Nodera Risa , Yoshioka Keiji 
Published: February 2024

Objective Cartilage degeneration is a key feature of osteoarthritis (OA) and rheumatoid arthritis and is thought to negatively impact patients’ quality of life. Diclofenac etalhyaluronate (DEH, SI-613/ONO-5704) is a hyaluronic acid (HA) derivative chemically bound to diclofenac (DF) that has been reported to improve OA symptoms; however, its effect on cartilage degeneration remains unknown. In the present study, we investigated the chondroprotective effect of DEH in rats with collagen-induced arthritis and interleukin-1β-stimulated human chondrocytes. Design Rats with collagen-induced arthritis were administered DEH and HA intra-articularly, and DF orally. Knee joint swelling, histological scores of articular cartilage, and inflammatory (Il1b) and catabolic (Mmp3 and Mmp13) gene expression in the synovial tissue and cartilage were evaluated. In vitro direct effects of DEH on matrix metalloproteinase (MMP)-3 and MMP-13 expression were examined in interleukin-1β-stimulated human chondrocytes. Results In a rat model of collagen-induced arthritis, a single intra-articular dose of DEH inhibited knee joint inflammation and cartilage degeneration. Daily oral administration of DF had similar effects. Conversely, HA administered as a single intra-articular dose had no effect. Only DEH inhibited Mmp3 gene expression in the cartilage, whereas DEH and DF inhibited Mmp3 and Mmp13 mRNA expression in the synovial tissue. In interleukin-1β-stimulated human chondrocytes, DEH and HA inhibited MMP-3 and MMP-13 production, whereas DF had no effect. Conclusions In this study, we demonstrated the chondroprotective effect of DEH in rats with collagen-induced arthritis and in interleukin-1β-stimulated human chondrocytes. Thus, DEH may suppress cartilage degeneration in patients with musculoskeletal diseases, such as OA.
The first reported mortality from aluminum phosphide poisoning in Lebanon: a case report
Authors: Edde Pierre , Kortbawi Anthony El , Halabi Zeina , Sakr Nancy , Barakat Alondra , Zahran Tharwat El 
Published: February 2024

Abstract
Background
Aluminum phosphide is a commonly used pesticide, particularly in developing countries where uncontrolled insecticides and pesticides are commonly prevalent. Mortalities have been reported due to accidental and suicidal exposures to aluminum phosphide. To date, there has been no reported mortality case of aluminum phosphide in Lebanon. In addition, there is no specific antidote for aluminum phosphide toxicity and the treatment is mainly supportive. This is why awareness should be spread about this case to include it in the differential diagnoses and enhance prompt management and response in future encounters.

Case presentation
A previously healthy 37-year-old male, presented to the emergency department of Notre Dame des Secours University Hospital Center for a suicidal attempt after ingesting 5 tablets of pesticide containing 56% aluminum phosphide an hour prior to presentation. Shortly after the presentation, the patient began deteriorating and became clinically unstable. The patient was then intubated and was started on sodium bicarbonate along with aggressive fluid resuscitation. The patient remained hypotensive even after giving vasopressors. He was then later admitted to the intensive care unit for further management. However, the patient further decompensated and developed multiorgan failure. This is the first case of mortality in Lebanon from aluminum phosphide toxicity.

Conclusions
Emergency physicians should include aluminum phosphide toxicity in the differential diagnosis when dealing with patients ingesting unknown pesticides especially when they smell the characteristic garlic-like odor. The toxicity from ALP leads to multiorgan failure and death rapidly. Thus, it is of utmost importance to start early, and aggressive resuscitation given that there is no specific antidote.
Ancestral alleles defined for 70 million cattle variants using a population-based likelihood ratio test
Authors: Dorji Jigme , Reverter Antonio , Alexandre Pamela A. , Chamberlain Amanda J. , Vander-Jagt Christy J. , Kijas James , Porto-Neto Laercio R. 
Published: February 2024

Abstract
Background
The study of ancestral alleles provides insights into the evolutionary history, selection, and genetic structures of a population. In cattle, ancestral alleles are widely used in genetic analyses, including the detection of signatures of selection, determination of breed ancestry, and identification of admixture. Having a comprehensive list of ancestral alleles is expected to improve the accuracy of these genetic analyses. However, the list of ancestral alleles in cattle, especially at the whole genome sequence level, is far from complete. In fact, the current largest list of ancestral alleles (~ 42 million) represents less than 28% of the total number of detected variants in cattle. To address this issue and develop a genomic resource for evolutionary studies, we determined ancestral alleles in cattle by comparing prior derived whole-genome sequence variants to an out-species group using a population-based likelihood ratio test.

Results
Our study determined and makes available the largest list of ancestral alleles in cattle to date (70.1 million) and includes 2.3 million on the X chromosome. There was high concordance (97.6%) of the determined ancestral alleles with those from previous studies when only high-probability ancestral alleles were considered (29.8 million positions) and another 23.5 million high-confidence ancestral alleles were novel, expanding the available reference list to improve the accuracies of genetic analyses involving ancestral alleles. The high concordance of the results with previous studies implies that our approach using genomic sequence variants and a likelihood ratio test to determine ancestral alleles is appropriate.

Conclusions
Considering the high concordance of ancestral alleles across studies, the ancestral alleles determined in this study including those not previously listed, particularly those with high-probability estimates, may be used for further genetic analyses with reasonable accuracy. Our approach that used predetermined variants in species and the likelihood ratio test to determine ancestral alleles is applicable to other species for which sequence level genotypes are available.
A comparison of embedding aggregation strategies in drug–target interaction prediction
Authors: Iliadis Dimitrios , De Baets Bernard , Pahikkala Tapio , Waegeman Willem 
Published: February 2024

AbstractThe prediction of interactions between novel drugs and biological targets is a vital step in the early stage of the drug discovery pipeline. Many deep learning approaches have been proposed over the last decade, with a substantial fraction of them sharing the same underlying two-branch architecture. Their distinction is limited to the use of different types of feature representations and branches (multi-layer perceptrons, convolutional neural networks, graph neural networks and transformers). In contrast, the strategy used to combine the outputs (embeddings) of the branches has remained mostly the same. The same general architecture has also been used extensively in the area of recommender systems, where the choice of an aggregation strategy is still an open question. In this work, we investigate the effectiveness of three different embedding aggregation strategies in the area of drug–target interaction (DTI) prediction. We formally define these strategies and prove their universal approximator capabilities. We then present experiments that compare the different strategies on benchmark datasets from the area of DTI prediction, showcasing conditions under which specific strategies could be the obvious choice.
Comparing the gut microbiota of Sichuan golden monkeys across multiple captive and wild settings: roles of anthropogenic activities and host factors
Authors: Liu Xuanzhen , Yu Jianqiu , Huan Zongjin , Xu Mei , Song Ting , Yang Ruilin , Zhu Wei , Jiang Jianping 
Published: February 2024

Abstract
Background
Captivity and artificial food provision are common conservation strategies for the endangered golden snub-nosed monkey (Rhinopithecus roxellana). Anthropogenic activities have been reported to impact the fitness of R. roxellana by altering their gut microbiota, a crucial indicator of animal health. Nevertheless, the degree of divergence in gut microbiota between different anthropogenically-disturbed (AD) R. roxellana and their counterparts in the wild has yet to be elucidated. Here, we conducted a comparative analysis of the gut microbiota across nine populations of R. roxellana spanning China, which included seven captive populations, one wild population, and another wild population subject to artificial food provision.

Results
Both captivity and food provision significantly altered the gut microbiota. AD populations exhibited common variations, such as increased Bacteroidetes and decreased Firmicutes (e.g., Ruminococcus), Actinobacteria (e.g., Parvibacter), Verrucomicrobia (e.g., Akkermansia), and Tenericutes. Additionally, a reduced Firmicutes/Bacteroidetes ratiosuggested diminished capacity for complex carbohydrate degradation in captive individuals. The results of microbial functional prediction suggested that AD populations displayed heightened microbial genes linked to vitamin and amino acid metabolism, alongside decreased genes associated antibiotics biosynthesis (e.g., penicillin, cephalosporin, macrolides, and clavulanic acid) and secondary metabolite degradation (e.g., naphthalene and atrazine). These microbial alterations implied potential disparities in the health status between AD and wild individuals. AD populations exhibited varying degrees of microbial changes compared to the wild group, implying that the extent of these variations might serve as a metric for assessing the health status of AD populations. Furthermore, utilizing the individual information of captive individuals, we identified associations between variations in the gut microbiota of R. roxellana and host age, as well as pedigree. Older individuals exhibited higher microbial diversity, while a closer genetic relatedness reflected a more similar gut microbiota.

Conclusions
Our aim was to assess how anthropogenic activities and host factors influence the gut microbiota of R. roxellana. Anthropogenic activities led to consistent changes in gut microbial diversity and function, while host age and genetic relatedness contributed to interindividual variations in the gut microbiota. These findings may contribute to the establishment of health assessment standards and the optimization of breeding conditions for captive R. roxellana populations.