Search Results (592)

Serratia species are Gram-negative pathogens responsible for a wide range of nosocomial infections. This multicenter nationwide retrospective study aimed to describe the epidemiology, clinical characteristics, antimicrobial susceptibility, and outcomes of Serratia infections in pediatric oncology patients and hematopoietic stem cell transplantation (HSCT) recipients in Poland between 2012 and 2023. A total of 36 Serratia infection episodes were identified in patients under 20 years of age, including 30 cases (83.3%) in the oncological (OHD) group and six (16.7%) among HSCT recipients. The median age was 4.30 years. The most common underlying diseases were acute lymphoblastic leukemia (36.1%) and central nervous system tumors (16.7%). Bloodstream infections predominated in OHD patients (33.3%), whereas urinary tract infections were most frequent in HSCT recipients (83.3%). S. marcescens was the most commonly isolated species. More than half of isolates (53.3%) showed antimicrobial resistance, with extended-spectrum β-lactamase (ESBL)-producing strains in 26.7% and AmpC β-lactamase-producing strains in 13.3%. Multidrug resistance occurred in 30%. Treatment most often included amikacin, piperacillin/tazobactam, and carbapenems. Five deaths occurred in the OHD group and one in the HSCT group, none directly related to Serratia infection. Although uncommon, Serratia infections remain clinically relevant due to their high antimicrobial resistance, underscoring the need for antimicrobial stewardship. Full article

Circulating tumor DNA (ctDNA) was initially conceived as a minimally invasive surrogate for interrogating cancer biology; however, three decades of evidence have demonstrated that plasma is not a passive reservoir of tumor-derived material, but rather a dynamic and biologically heterogeneous milieu in which multiple competing genomic signals coexist. This review explores the level of interpretive rigor required to translate ctDNA detection into clinically actionable precision oncology. Clonal hematopoiesis of indeterminate potential (CHIP) is discussed not as an occasional confounder, but as an intrinsic source of biological background noise, underscoring the critical importance of matched leukocyte sequencing to discriminate tumor-derived alterations from hematopoietic variants, particularly in older individuals and in patients previously exposed to cytotoxic therapies. The widespread assumption that variant allele frequency (VAF) directly reflects tumor burden is critically re-evaluated through the mathematical relationships linking VAF to tumor fraction, local copy-number architecture, and mutation multiplicity. Within this framework, estimation of cancer cell fraction (CCF) and probabilistic discrimination between clonal and subclonal events are examined, including the emergence of reversion mutations as molecular evidence of therapy-driven evolutionary adaptation. The review also addresses the central paradox of ultra-sensitive sequencing technologies: although unique molecular identifiers and duplex sequencing can extend analytical sensitivity below 0.01% VAF, sensitivity in the absence of contextual specificity risks conflating technical artifacts and biologically insignificant alterations with clinically meaningful disease. Equal emphasis is placed on pre-analytical variables, highlighting how sample collection, stabilization, and processing protocols define the upper limit of downstream analytical reliability. Beyond single-nucleotide variants, fragmentomic and methylation-based approaches are presented as complementary orthogonal dimensions capable of revealing tumor-associated signals even when mutational evidence is limited or absent. Longitudinal ctDNA assessment is argued to provide substantially greater biological and clinical insight than isolated static measurements, while robust clinical reporting is shown to depend on transparent disclosure of assay limitations, residual uncertainty related to CHIP, and structured bidirectional communication between molecular laboratories and treating clinicians. Ultimately, the transition from a biomarker-centered model toward an integrated systems-based framework, combining genomics, epigenomics, fragmentomics, and evolutionary modeling, emerges as the defining challenge for the next generation of liquid biopsy in precision oncology. Full article

CD19 chimeric antigen receptor (CAR) T cells have demonstrated promising outcomes in B-cell malignancies. However, using pretreated autologous T cells currently faces limitations, including compromised T-cell fitness and the challenge of manufacturing sufficient cell numbers for treatment. Consequently, natural killer (NK) cells have emerged as an alternative due to their natural ability to mediate cytotoxicity and their favorable safety profile. This study aims to generate patient autologous hematopoietic stem cell-derived NK (HSC-NK) cells and assess their therapeutic potential compared to peripheral blood NK (PB-NK) cells. We successfully cultivated HSC-NK under a 28-day, two-step differentiation and expansion protocol, achieving a cumulative 290-fold expansion using optimized memory-like cytokines and feeder cell stimulation. The expanded HSC-NK cells demonstrated a distinct phenotype (CD56⁺CD16^low), representing an immature differentiation state, characterized by a lower expression of inhibitory receptors (NKG2A, KIR2DL, and CD94) and the exhaustion markers (LAG3, PD-1, TIM-3, and CTLA-4) compared to PB-NK cells. Prominent expression of CD62L, alongside sustained expression of CD69 and CD107a, was observed, translating into NK cell proliferation, activation, and cytotoxicity against cancer cells comparable to PB-NK cells. In conclusion, generating HSC-NKs is feasible while preserving essential NK cell phenotypes and activities. Our findings emphasize the potential of HSCs as an alternative NK cell source for cancer immunotherapy. Full article

Multidrug-resistant (MDR) pathogens present a significant threat to hematopoietic stem cell transplant (HSCT) recipients; despite their critical implications, regional data on their infection patterns remain scarce. This study aimed to characterize the incidence, pathogen and antimicrobial resistance distribution of clinically confirmed bacterial infections among HSCT recipients. A retrospective analysis was conducted at King Hussein Cancer Center, Jordan (2018–2022). MDR pathogens were defined per CDC criteria. During the study period, 1157 HSCT procedures were performed. A total of 327 patients developed clinically documented bacterial infections, yielding an overall cumulative incidence of 28.3%, with a higher burden in the pediatric cohort (34.7%), including exclusive identification of Klebsiella oxytoca in pediatrics (2.3%). Gram-negative bacteria dominated, with Escherichia coli (50.5%) and Klebsiella pneumoniae (22.0%) being most common. Extended-spectrum beta-lactamase (ESBL) production was the dominant resistance mechanism (71.3%), followed by carbapenem-resistant Enterobacteriaceae (CRE; 14.1%), methicillin-resistant Staphylococcus aureus (MRSA; 8.6%), and carbapenem-resistant Pseudomonas aeruginosa (CRPA; 7.0%). The urogenital (39.1%) and bloodstream (31.2%) were the most infected sites. Significant site-specific associations were noted for ESBL production, MDR-Acinetobacter baumannii (p < 0.001) and MRSA (p = 0.007). Temporal analysis revealed a convergent MDR peak in 2021. Our findings offer critical insights into MDR pathogen incidence in HSCT recipients in the Middle East, informing improved infection management and intensified antimicrobial stewardship in this high-risk population. Full article

The prognosis of mucormycosis after hematopoietic stem cell transplantation (HSCT) is generally poor but data on post-HSCT outcomes in patients with pre-HSCT mucormycosis are limited. We reviewed patients with documented mucormycosis at MD Anderson Cancer Center (2008–2024) and identified five patients who subsequently underwent HSCT. A literature review identified 24 additional such cases. Most patients had acute myeloid leukemia (69%). The most common site of mucormycosis was pulmonary (59%), while 31% had disseminated mucormycosis. All patients received antifungals and 76% had surgery prior to HSCT. At the time of HSCT, 67% had mucormycosis responding to treatment. No patient went to transplant with progressing mucormycosis. Eighty percent of patients with ≥12 months of follow-up after HSCT were alive. Five of the twenty-nine patients (17%) had documented or suspected mucormycosis recurrence post-HSCT. Relapsed malignancy pre-HSCT was associated with increased 12-month post-HSCT mortality (p = 0.031). Furthermore, post-transplant mortality was higher in cord blood recipients (p = 0.019) and tended to be higher in patients not undergoing surgery pre-HSCT (p = 0.062). Despite publication bias, our data suggest that HSCT can be conducted safely in selected patients with pre-HSCT mucormycosis, particularly when underlying hematologic malignancy is in remission, mucormycosis is stable, and surgical source control is feasible. Full article

Targeting checkpoints is one of the most promising strategies in cancer chemotherapy. Leukemia, in particular, is expected to yield high therapeutic efficacy due to its high replication stress. However, the DNA damage response factors involved in the vulnerability to checkpoint inhibitors of these hematopoietic cancers remain elusive. In this study, we reveal common factors required for cellular resistance to ATR inhibition in hematopoietic cancer cells. We explored the DNA damage response pathways contributing to cellular tolerance to three types of ATR inhibitors using an isogenic DNA repair factor mutant collection derived from the chicken lymphoma cell line, DT40. We first demonstrated significant ATR inhibition activity of the recently developed Torin2 analogous compounds, SPK67 and SPK98, under stressed replication conditions. We then compared cellular sensitivity patterns of the known ATR inhibitor, VE-821, and the potential ATR inhibitors, SPK67 and SPK98, in 24 types of mutants deficient in genome maintenance systems and found that RAD17^/−, FEN1^−/−, and POLB^−/− cells exhibited hypersensitivity to all these drugs. Consistently, these mutant cells exhibited increased chromosome instability upon treatment with VE-821, SPK67, and SPK98, resulting in apoptosis. These results suggest that Rad17, Fen1, and Polymerase β play roles in responding to DNA damage caused by these drugs. However, ATR inhibition did not result in cell-cycle arrest, Chk1 phosphorylation, or increased γH2AX levels. These results suggest that, although ATR inhibition causes DNA damage, impaired checkpoint function suppresses the appropriate activation of DNA damage signaling pathways, thereby leading to cell death. This study is the first to demonstrate the importance of Rad17, Fen1, and Polymerase β in cellular tolerance to ATR inhibition in hematopoietic cells. Full article

Background/Objectives: Cell-free DNA (cfDNA) end-motifs (EDMs) are promising fragmentomic features for noninvasive cancer detection; however, their diagnostic utility may be limited by background signals from abundant hematopoietic-derived cfDNA fragments. Existing EDM-based approaches, including the Motif Diversity Score (MDS) and classifiers based on raw motif frequencies, often show limited robustness across different datasets. Methods: To address this limitation, we developed a frequency-domain analytical framework based on the Discrete Fourier Transform (DFT), converting k-mer EDM frequency profiles into amplitude spectral features. We further constructed a stacking-based Ensemble Spectral Model (ESM) integrating multi-scale spectral features from 4–6-mer EDMs. Results: The framework was evaluated using 1782 plasma cfDNA samples from four independent studies comprising six datasets. Raw EDM profiles showed extremely high similarity between cancer and non-cancer samples (mean Spearman R = 0.999). Following DFT transformation, amplitude spectra showed improved separability between groups. Across datasets, the ESM achieved a mean AUC of 0.843, representing a 15.0% improvement over raw 4-mer EDM-based SVM models and a 56.4% improvement over the MDS. At 95% specificity, mean sensitivity reached 0.585, exceeding those of the raw EDM (0.418) and MDS (0.195). Frequency-guided motif attribution further linked spectral features to sequence-level motif patterns and potential regulatory programs. Conclusions: Frequency-domain transformation improves the representation of cfDNA EDM profiles and provides a robust analytical framework for cross-dataset cancer detection. Full article

Single-cell RNA sequencing (scRNAseq) captures unique profiles of individual cells and uncovers cell-to-cell communication (CCC) through ligand–receptor (LR) interactions. Moreover, it reveals signalling mechanisms underlying cellular heterogeneity and complexity in downstream responses in healthy and disease states. In this work, we developed a composite computational pipeline to track CCC patterns in the tumour microenvironment (TME) during Multiple Myeloma (MM) progression as a case study. Three publicly available scRNAseq datasets were analysed using basic single-cell analytics and stage-specific CCC networks were reconstructed with CellChat, in a microenvironment-specific approach. Basic network analytics (CytoHubba) were performed to identify key cell nodes based on network topology metrics; differential network rewiring (DyNet) was performed to calculate rewired nodes. Follow-up analyses were conducted with NicheNet to investigate downstream responses and target genes influenced by CCC. Our network analyses highlighted dendritic cells (DCs), plasmacytoid DCs (pDCs), hematopoietic stem cells (HSCs), red pulp macrophages (RPMs), natural killer (NK) cells, and T and B cells as important cell nodes. Moreover, in neutrophils, the HLA-DRA–JUN–FOS was shown to play a key role in the progression of monoclonal gammopathies of uncertain significance (MGUS) to active MM by supporting cancer hallmarks and MM pathophysiology. To conclude, our work suggests an explanatory–computational pipeline that incorporates well-known frameworks in a hypothesis-driven scope, which leads to results relevant to the pathophysiology of MM. Full article

APR-246 (Eprenetapopt) is a small-molecule drug that restores the activity of dysfunctional p53 proteins caused by missense mutations that affect the DNA-binding domain. However, recent studies suggest that APR-246 can also induce cell death in cancer cells that carry wild-type (WT) TP53. Here, we aimed to determine the impact of APR-246 on the survival of acute myeloid leukemia (AML) cells using isogenic Molm13 cells that harbor WT TP53, a missense mutation of TP53^R175H, or a biallelic deletion of TP53 (TP53^−/−). Our results showed that Molm13 TP53^−/− cells were significantly more resistant to APR-246-induced cell death compared with their Molm13 TP53^R175H/− mutant and Molm13 TP53^+/+ counterparts. In addition, knockdown of TP53 significantly reduced cytotoxicity induced by APR-246 in two TP53 WT AML cell lines (MV4-11 and OCI-AML2). Moreover, APR-246 markedly decreased the clonogenicity of TP53 WT hematopoietic stem/progenitor cells (HSPCs) isolated from humans and mice. In contrast, biallelic loss of TP53, but not TP53 missense mutation, significantly increased the resistance of mouse HSPCs to APR-246. Mechanistically, the loss of functional p53 proteins in Molm13 and MV4-11 cells decreased intrinsic apoptosis and impaired the production of cellular reactive oxygen species (ROS) induced by APR-246. Together, our results indicate that, in at least a subset of AML cell lines and normal HSPCs, APR-246-induced ROS production and cytotoxicity are enhanced in the presence of WT p53 proteins. Full article

Background: Chemotherapy and radiation accelerate aging of multiple systems, including the immune and musculoskeletal systems. Resistance training may mitigate some of the late physiologic effects of cancer therapy. Methods: We developed a community-based pilot study of resistance training for long-term cancer survivors meeting criteria for pre-frailty or frailty (N = 8; 6 allogeneic hematopoietic cell transplant, 1 autologous hematopoietic transplant, 1 breast cancer survivor) and their caregivers (N = 8 healthy controls) consisting of a baseline assessment, 10 weeks of personalized resistance training at least once weekly as a group and as many additional times on an individual basis as their schedule allowed, and an end-of-study assessment to measure change in strength and body composition. Blood samples were collected at the start of the study and after the 10-week training program to assess changes in peripheral blood mononuclear cell DNA methylation patterns, gene expression measured by RNA sequencing, and stool microbiome analysis using metagenomics. The median number of resistance training sessions was 25 sessions. Results: Cancer survivors and controls both more than doubled their squat and press volume after 10 weeks. At baseline, cancer survivors exhibited a pro-inflammatory transcriptomic and epigenetic profile with elevated interferon signaling and reduced naïve T cell signatures compared to healthy controls, consistent with immune senescence. After 10 weeks of resistance training, these differences normalized, suggesting that exercise exerted anti-inflammatory and immune-restorative effects in cancer survivors at both gene expression and methylation levels. Ten fecal microbial pathways that were lower in relative abundance in patients compared with controls at baseline were no longer significantly different post-exercise. Conclusions: Our data suggest that in addition to beneficial changes in body composition, resistance training may exert an immune restorative effect in cancer survivors. Full article

Background: Colorectal cancer is a common malignancy and 5-fluorouracil (FU) remains a mainstay of chemotherapy despite its toxicity. As an important part of comprehensive tumor treatment, dual-protein (DP) nutritional intervention is attracting more and more attention. Methods: This study preliminarily evaluated the regulatory effects of DP intervention on colorectal cells of CT26 tumor-bearing mice, examining the dosage and administration methods of DP, as well as the anti-tumor effects of FU alone or in combination with DP. Results: The results showed that low- and medium-dose DP numerically increased spleen index and showed trends toward alleviating FU-induced thymic atrophy, splenic damage, nephrotoxicity, and myocardial injury. It also partly mitigated muscle wasting, prevented FU-induced shortening of the colorectal tract, and reduced intestinal injury. In addition, DP was associated with increased lymphocyte, monocyte, and platelet counts and decreased granulocytes, suggesting possible alleviation of chemotherapy-induced bone marrow suppression and a potential effect on hematopoietic function. Flow cytometry results indicated possible effects of DP on CD4⁺ T and CD8⁺ T cell proliferation or apoptosis, modulation of effector and memory phenotypes, reduced splenic neutrophil levels, balanced B cell function, and maintained natural killer cell activity. In addition, DP intervention also showed trends toward regulating hepatic lipid metabolism and partially alleviating FU-induced dyslipidemia and muscle damage. In addition, DP and FU could increase IL-2, IL-10, GM-CSF and IFN-γ and decrease IL-6 and TNF-α. Conclusions: In conclusion, a moderate dose (0.67 g/kg) of DP had the most favorable trends, and the pre-intervention mode was more effective. This study also provided exploratory data on the potential of DP in reducing chemotherapy-related toxicity. These findings will provide preliminary scientific support for nutritional therapy in colorectal cancer patients, as well as for the research, development, and application of dual-protein foods for special medical purposes. Full article

Background: Cytokine-induced JAK–STAT signaling becomes dysregulated in chronic human diseases, including cancer and autoimmunity, and contributes to immune cell dysfunction. A cytokine-independent approach to activating STAT proteins could “hardwire” pro-survival and effector programs in immune cells to sustain function within diseased tissues. Engineered variants of the herpesvirus saimiri tyrosine kinase interacting protein (TIP) can recruit the SRC family kinase (SFK) LCK to drive STAT phosphorylation and activation. Here, we evaluated the interactome of a TIP-derived, cytokine-independent STAT5 activator and determined whether it could induce STAT5 activation in immune cell lines and primary human CD8+ T cells. Methods: A STAT5 activator (aSTAT5) was characterized by proteomics using affinity purification mass spectrometry (AP-MS) to define its interactome and STAT5 binding specificity. STAT5 phosphorylation was assessed in hematopoietic cell lines and primary human CD8+ T cells. Results: Proteomic analysis confirmed preferential association of aSTAT5 with STAT5 relative to other proteins. In cell-based assays, aSTAT5 induced robust STAT5 phosphorylation in LCK-expressing NK-92 and Jurkat T cells, whereas phosphorylation was not observed in Raji B cells or RAW 264.7 macrophages despite expression of closely related SFKs and STAT5. Cytokine-independent STAT5 phosphorylation supported the viability of NK-92 cells and primary human CD8+ T cells during cytokine withdrawal and preserved the cytotoxic function of CAR T cells. Conclusions: We defined the interactome of a cytokine-independent STAT5 activator and demonstrated its capacity to maintain survival and function in human CD8+ T cells and NK-92 cells. These findings underscore the translational potential of engineered, cytokine-independent STAT5 activation for immune cell therapies. Full article

Background: Cancer is common among patients with acute myocardial infarction (AMI) and may influence management and outcomes. The prognostic impact of cancer status (active vs. past) and its anatomical site remains insufficiently defined. We evaluated the association between cancer and short- and long-term outcomes after AMI in a large population cohort. Methods: Using linked administrative databases from Lombardy, Italy, we identified adults with a first AMI hospitalization from 2014 to 2022 (N = 124,403). Patients were categorized by cancer history, cancer status (active vs. past), and cancer site. The primary endpoint was in-hospital mortality; secondary endpoints were 1-year all-cause mortality and 1-year rehospitalization for AMI or acute heart failure (AHF). Multivariable log-binomial, Cox, and Fine&Gray models were applied. Results: Overall, 18,463 (14.8%) had a history of cancer. They were older and had higher comorbidity burden. Cancer history was associated with higher in-hospital mortality (adjusted risk ratio [RR] 1.06, 95% CI 0.99–1.13) and one-year mortality (adjusted hazard ratio [HR] 1.46, 95% CI 1.40–1.52). Active cancer carried the greatest risk (in-hospital RR 1.07, 95% CI 1.00–1.15; 1-year HR 1.60, 95% CI 1.53–1.68), whereas past cancer showed no excess mortality. Site-specific analyses identified lung (one-year HR 2.69, 95% CI 2.15–3.37) and hematological cancers (one-year HR 2.19, 95% CI 1.88–2.56) as highest-risk. Elevated mortality with cancer was consistent in STEMI and NSTEMI. Competing-risk analyses showed a similar risk of rehospitalization among cancer and non-cancer patients. Conclusions: In a real-world, unselected AMI population, cancer worsens short- and long-term survival, especially when active and involving the lungs or the hematopoietic tissues. Incorporating cancer status into AMI risk stratification and strengthening cardio-oncology pathways in acute care are warranted to improve patient outcomes. Full article

Background/Objectives: Using real-world data, this study evaluates the use of ADCs over a decade across six University of California (UC) medical centers, focusing on the incidence of neutropenia-related adverse effects and associated clinical outcomes. Methods: A real-world retrospective study utilizing UC Health Data Warehouse records of patients receiving at least one dose of the ten most-used ADCs at one of the 6 UC hospitals between 2012 and 2024. The outcomes evaluated in this study were grade 3+ neutropenia and febrile neutropenia (FN) during any treatment cycle, and healthcare utilization outcomes including G-CSF prophylaxis, hospital and ICU admission, and mortality. Multivariate logistic regression was conducted to identify predictors for neutropenia-related events after the first dose of ADC. Results: Data from 3511 patients (mean ± SD age: 56.7 ± 17.6 years) were analyzed. The most commonly observed cancer types were breast cancer (43.4%), lymphoid, hematopoietic (41.8%), and urinary tract cancer (13.4%). The top three most commonly prescribed ADCs were fam-trastuzumab deruxtecan (22.6%), ado-trastuzumab emtansine (19.4%), and brentuximab vedotin (18.1%). Their respective all-cycle rates of FN were 5.4%, 1.2%, and 10.4%, while grade 3+ neutropenia rates were 16.4%, 5.1%, and 40.1%. Gemtuzumab ozogamicin and inotuzumab ozogamicin were associated with the highest rates of FN (both 18.1%), and inotuzumab ozogamicin was associated with the highest rates of hospital admissions (27.1%), ICU admissions (3.8%), and deaths (5.2%). Anemia and immunodeficiency disorders were identified as predictors for first-dose FN among patients receiving ADCs. Conclusions: Real-world data from this large multi-center cohort showed substantial variation in neutropenia-related events across ADCs. As ADC use continues to grow, these findings highlight the need for vigilant monitoring and proactive supportive care. Full article