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IFN-γ/JAK/STAT axis awakens the delta force of hemoglobin

General and selective ruthenium-catalyzed hydrogenation of primary amides to primary amines under mild conditions

Twenty years of ungulate disease surveillance by the Canadian Wildlife Health Cooperative (2003–2022)

Free-ranging wild ungulates are integral to the health and well-being of Canadian socioecological systems, contributing various One Health benefits (e.g., nutrient cycling, sustainable food resources) to the people and other animals that coexist with them. In North America, ungulates face a range of threats to their population health. To address knowledge gaps surrounding the health of Canadian ungulates, we conducted a retrospective analysis of 20 years of ungulate morbidity and mortality data collected through passive disease surveillance conducted by the Canadian Wildlife Health Cooperative (CWHC) and through submissions from collaborative partners. In total, 2525 cases across 12 species were assigned a category of diagnosis (COD) by a CWHC veterinary pathologist. Infectious/ inflammatory/ transmissible CODs accounted for 53.0% of all cases, with two diagnoses made most frequently: chronic wasting disease (CWD) and Parelaphostrongylus tenuis ( P. tenuis ) infection. We identified a significant increase in the proportion of cervid cases diagnosed with CWD in Saskatchewan that was consistent across species, with the odds of an individual cervid in Saskatchewan being CWD positive increasing by 22% per year. We also detected a significant increase in the proportion of moose ( Alces americanus ) cases diagnosed with P. tenuis , and this trend was consistent across endemic regions in Canada. Emerging diseases were also detected for the first time through our surveillance approach (e.g., the first Ontario cases of epizootic hemorrhagic disease virus, detected in white-tailed deer ( Odocoileus virginianus )). Trauma (15.3%) and emaciation (8.9%) were the most frequently assigned non-infectious CODs. We highlight potential disease threats to SAR that may emerge secondary to changing distributions of sympatric ungulate species and the pathogens they carry (e.g., CWD positive deer/elk within known caribou ranges in Saskatchewan). Our results highlight the strengths of passive disease surveillance, as well as the need for an integrated, holistic wildlife surveillance approach in Canada.

Could a TCR be faster than a CAR?

Plastic deformation in nanodiamonds

Retraction: Image-guided procedures in the hybrid operating room: A systematic scoping review

Targeting BCMA: a double-edged sword for infection risk

Genetic variations interact with polybrominated diphenyl ether exposure to alter lipid homeostasis

Glycemic trajectories of fasting blood glucose on the pathological responses in breast cancer women with and without concomitant diabetes

Background Most existing studies have predominantly examined the impact of single blood glucose measurements without considering how fluctuations over time may influence clinical outcomes. Moreover, no studies have yet explored the effect of blood glucose trajectories on pathological responses in breast cancer patients undergoing neo-adjuvant chemotherapy (NACT), highlighting a significant gap in the current literature. Purpose To determine the impact of dynamic changes in blood glucose during neo-adjuvant chemotherapy on the pathological responses in women with breast cancer, with and without concomitant diabetes. Method This prospective cohort study was conducted among women with locally advanced breast cancer receiving treatment at GINUM Hospital in Gujranwala, Pakistan. Data for the prospective phase were collected from 20 January 2023 to–13 May 2024. Clinical data were obtained using a structured data collection form. Diabetes status was confirmed at baseline using Glycated hemoglobin (HbA1c) and Fasting blood glucose (FBG) tests. Patients were classified into glycemic trajectories based on the values of their FBG values during the treatment period. Results Five blood glucose trajectories were identified from the start of breast cancer treatment to the post-treatment period: normal glycemic trajectory (23 patients, 4.1%), erratic glycemic trajectory (130 patients, 23.2%), consistently hyperglycemic trajectory (127 patients, 22.7%), controlled diabetes (130 patients, 23.2%), and uncontrolled diabetes (150 patients, 26.8%). All glycemic trajectory groups demonstrated a non-significant increase in the odds of achieving Pathological partial response (pPR). Similar to pPR, the various categories of blood glucose trajectories were associated with a non-significant increase in the odds of Pathological no response (pNR). Among nondiabetic patients the group I(normal) and group III (consistently hyperglycemic) trajectories showed no significant interaction with pathological responses, as indicated by repeated measures ANOVA. Conclusion Our findings indicated that fluctuations in FBG levels among individuals with diabetes were not associated with pathological responses to neo-adjuvant chemotherapy. This suggests that the rise in blood glucose levels in diabetic patients are more likely driven by their pre-existing metabolic dysfunction rather than their chemotherapy related pathological responses.

A CD22-specific T-cell receptor enables effective adoptive T-cell therapy for B-cell malignancies

Abstract CD19 chimeric antigen receptor (CAR) T-cell therapy has become the standard of care in relapse and/or refractory B-cell malignancies. Up to 30% to 60% of patients experience relapsed disease because of the emergence of CD19low or CD19− tumor cell clones. Although bispecific CD19/CD22 CAR T cells have been explored, limited persistence and antigen downregulation of CD19 and/or CD22 have compromised their efficacy in relapsing patients. A comprehensive analysis of CD22 expression revealed that CD22 is ubiquitously expressed across all subgroups of B-cell lymphomas and B-cell leukemias, establishing CD22 as a valuable immunotherapeutic target. Using a humanized mouse model with a diverse human T-cell receptor (TCR) repertoire, we identified a high-affinity TCR targeting a CD22 epitope presented by HLA-A∗02:01. In vitro, this TCR demonstrated high specificity and efficacy in both CD22+ cell lines and primary patient-derived tumor samples. Importantly, CD22 TCR T cells outperformed CD22 CAR T cells in recognizing cells with low CD22 surface expression, including CD22low Nalm6 cells that emerged after in vivo CD19 T-cell treatment. Unlike CD22 CAR T cells, CD22 TCR T cells effectively recognized tumor cells that predominantly express intracellular CD22. Notably, in vivo validation in a Nalm6 B-cell leukemia model confirmed the superior activity of CD22 TCR T cells against CD22low cells compared to CD22 CAR T cells. In conclusion, our findings provide strong preclinical evidence supporting CD22 TCR-based therapy as a potent treatment option for CD22low B-cell malignancies, including patients who relapsed after CD19 CAR T-cell therapy.

A gut microbiome-kidney-heart axis predictive of future cardiovascular diseases

Abstract Cardiovascular diseases (CVD) remain a major global health challenge. Early markers of disease initiation and progression are urgently needed. We, and others, have previously shown changes in the gut microbiome in association with metabolic and CVD. Here, we demonstrate that gut microbiome-related changes can be detected in association with subclinical variations in heart and kidney function. Markers related to gut microbial metabolism of aromatic amino acids, phenylalanine and tyrosine, associate with circulating pro-atrial natriuretic peptide and estimated glomerular filtration rate in a metabolically healthy European population. Observational and genetic evidence further identify microbiome-related metabolites as mediators of this gut microbiome-kidney axis, with their baseline levels associating with incident CVD in an external Canadian population. Altogether, our work suggests that the gut microbiome interacts with the cardiorenal axis and participates in an interorgan crosstalk affecting host physiology and risk of CVD.

EpCAM silencing suppresses aggressive phenotypes and induces partial redifferentiation in anaplastic thyroid cancer cells

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a dismal prognosis. Although recent advances in targeted therapies have modestly improved survival, the molecular mechanisms driving ATC progression remain incompletely elucidated. Epithelial cell adhesion molecule (EpCAM), a multifunctional cell-surface protein, is implicated in proliferation, migration, and stemness in various cancers. However, its role in thyroid cancer progression remains unclear. In this study, we investigated the function of EpCAM in thyroid cancer cell lines of varying differentiation status. EpCAM expression was significantly elevated in ATC cell lines compared with differentiated thyroid cancer (DTC) lines. EpCAM knockdown by siRNA suppressed proliferation, adhesion, motility, and invasion in ATC cells, but had minimal effects on DTC cells. Morphological analyses revealed that EpCAM silencing induced differentiation features, including follicle-like structure formation and increased expression of thyroid differentiation markers such as thyroglobulin and PAX8 in ATC cells. Furthermore, EpCAM inhibition decreased mesenchymal marker expression, reduced filopodia formation, and suppressed extravasation of cancer cells into the lung in an in vivo mouse model. Mechanistically, EpCAM knockdown attenuated epithelial–mesenchymal transition (EMT)-related pathways but did not affect major proliferation signaling cascades in ATC cells. These findings suggest that EpCAM promotes dedifferentiation and metastatic potential in ATC through EMT modulation. Our results provide new insights into the role of EpCAM in thyroid cancer biology and highlight its potential as a therapeutic target in ATC. Further studies are warranted to elucidate the mechanisms linking EpCAM to anaplastic transformation and to explore the therapeutic efficacy of EpCAM-targeting strategies in aggressive thyroid cancers.

Focal MPN-associated <i>JAK2-</i> mutated skeletal lesion with normal blood counts and bone marrow

DiNovo enables high-coverage and high-confidence de novo peptide sequencing via mirror proteases and deep learning

Identification of prognostic genes associated with tolerogenic dendritic cells in gastric cancer based on transcriptomic data

Background Tolerogenic dendritic cells have a pivotal function in treating autoimmune illnesses, atopic diseases, and neoplasms. The precise mechanism by which Tolerogenic dendritic cells function in gastric cancer remains incompletely understood. Therefore, this research explored potential genes with prognostic value related to Tolerogenic dendritic cells in gastric cancer, to identify novel therapeutic targets that could provide valuable insights for the clinical treatment of gastric cancer. Results Five prognostic genes (CXCL1, INHBA, ASCL2, RNASE1, and GPX3) were finally obtained to construct the risk model. Immune infiltration analysis revealed that GPX3 exhibited significant positive associations with various immune cell populations, particularly regulatory T cells. While ASCL2 was weakly associated with almost all immune cells. These results suggested that there was a complex correlation between prognostic genes and immune cells. The analysis of drug sensitivity demonstrated higher IC50 values for compounds such as BIBW2992 in high-risk group relative to low-risk group. A reverse pattern was observed for GSK269962A and similar drugs, which showed significantly higher IC50 values in low-risk group than high-risk group. Conclusion The present study revealed five prognostic genes and constructed a predictive model, which provided a theoretical basis for the correlation linking Tolerogenic dendritic cells to gastric cancer, and established potential therapeutic strategies in managing gastric cancer. Single-cell analysis revealed that INHBA, ASCL2, and CD36 exhibited marked differential expression in dendritic cells.

Pediatric hemophagocytic lymphohistiocytosis: current conceptualization, diagnosis, and treatment

Abstract Pediatric hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, characterized by heightened T-cell activation and overwhelming interferon gamma production. Rather than a binary “primary” vs “secondary” framework, it is best conceptualized as a threshold phenomenon that occurs when combined genetic and environmental factors exceed a critical tipping point, leading to a recognizable clinical pattern of abnormal immunopathology. In addition to classic genetic cytotoxic defects, an increasing number of genetic lesions continue to be recognized as related to HLH. Environmental triggers frequently include malignancy, infection, and rheumatologic disorders, and identifying underlying factors driving HLH is a crucial component of evaluation. The revised HLH-2004 criteria are an important tool in promptly recognizing HLH, but clinical criteria may be fulfilled by other inflammatory disorders. Genetic and functional immune testing are complementary tools for diagnosis and establishing recurrence risk. Dexamethasone and etoposide remain cornerstones of initial therapy but are best used in an individualized, response-based manner with close monitoring of inflammatory markers. Newer, more targeted agents continue to emerge and are often critical additions for achieving disease control. Most patients with inherited cytotoxic defects and other select causes require hematopoietic cell transplant for cure, which should occur as soon as feasible once adequate, not perfect, HLH control is established to minimize risk of reactivation, infection, and toxicity. This review aims to highlight key advancements in defining, diagnosing, and treating HLH based on a growing understanding of HLH pathophysiology. We also provide perspectives on practical clinical approaches that may be useful for diagnosing and treating pediatric HLH.

Integrated electrochemical porous solid electrolyte reactor and packed bed reactor for efficient synthesis of nylon-6 precursor

Cognitive load and teachers’ innovative behavior in AI-enhanced English language instruction: A mediation analysis of technological adaptability

This investigation examines the complex interrelationships between teachers’ cognitive load, technological adaptability, and innovative teaching behavior in AI-enhanced educational environments. Through the integration of Cognitive Load Theory, Technology Acceptance Model, and Innovation Diffusion Theory, we develop a sophisticated theoretical framework for understanding how cognitive demands influence teaching innovation through adaptive mechanisms. Employing exploratory structural equation modeling with WLSMV estimation (N = 600), we analyze data collected through rigorously validated instruments measuring AI-assisted Teaching Cognitive Load (ATCL), technological adaptability, and innovative teaching behavior. Results reveal a significant negative relationship between cognitive load and innovative teaching behavior ( β  = −.134, p &lt; .001), mediated by technological adaptability (indirect effect β  = −.171, p &lt; .001). The measurement model demonstrates exceptional psychometric properties (α = .91−.93; AVE = .64−.68) and establishes measurement invariance across teacher subgroups (ΔCFI ≤ .001). These findings advance theoretical understanding of cognitive-adaptive mechanisms in technology-enhanced teaching while providing empirically validated pathways for enhancing pedagogical innovation. The study contributes methodologically through the development of the ATCL scale and analytically through sophisticated mediation analysis techniques. Implications extend to professional development strategies, institutional policy formulation, and the theoretical conceptualization of cognitive load in AI-enhanced educational environments.

Hemophagocytic lymphohistiocytosis in adults

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder characterized by unchecked immune activation and hyperinflammation, resulting in end-organ tissue damage and high mortality rates in untreated patients. Since the first description of this condition in 1939, our understanding of HLH has continued to deepen, with increasing appreciation of the differences and similarities between primary (familial) HLH and secondary (acquired) HLH. Primary HLH typically presents in the early years of life on the backdrop of inherited genetic mutations affecting cytotoxic immune cell function, whereas secondary HLH more commonly presents in adults and is a heterogeneous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. However, they converge in a common pathway of widespread systemic inflammation, which clinically manifests with fevers, organomegaly, cytopenias, laboratory derangements, and rapid development of multiorgan failure. As such, early recognition and intervention is critical to prevent irreversible organ damage and death in both primary and secondary HLH. In this review, we focus our attention on adult-onset secondary HLH and explore the latest updates on the pathophysiology, precipitants, clinical presentation, diagnosis, and management of this life-threatening condition. Primary HLH is reviewed separately as a companion article in this review series.

Bio-inspired asymmetric Zn-N2O2 single-atom catalysts via natural skeleton for efficient N-alkylation of nitroarenes with alcohols

Abstract Although significant developments are made in non-noble metal catalysts for N-alkylation of nitroarenes with alcohols via borrowing hydrogen strategy, obtaining catalysts with superior activity, reusability and broad substrate scope under mild reaction conditions remains challenging. Single-atom catalysts (SACs) hold unique coordination/electron structures, to be the potential candidates for this reaction. In this study, we firstly and creatively fabricate bio-inspired Zn SACs with asymmetric Zn-N 2 O 2 sites by utilizing the natural skeleton of biomass chitosan (denoted as Zn/CS), and achieve the first instance of heterogeneous Zn SACs in borrowing hydrogen reaction between nitroarenes and alcohols. The results reveal that the asymmetric Zn-N 2 O 2 sites induced by natural skeleton (like ligands) and nanoporous structure of Zn/CS significantly promote the N-alkylation efficiency of nitroarenes with alcohols. Notably, the Zn/CS exhibits the highest turnover frequency (TOF) among the reported heterogeneous catalysts, as well as wide substrate scope (56 examples) and excellent reusability. Furthermore, the catalytic pathway/mechanism is investigated by combing theoretical calculations, which reveals that the asymmetric Zn-N 2 O 2 sites with electron-deficient character can facilitate the formation of Zn-H and Zn-O bonds between Zn/CS and Ph-CH 2 O − , thus easily generating the transition state Ph-CH 2 O* and driving the whole reaction.