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Preoperative staging of rectal cancer: the MERCURY research project.

The development of a surgical technique that removes the tumour and all local draining nodes in an intact package, namely total mesorectal excision (TME) surgery, has provided the impetus for a more selective approach to the administration of preoperative therapy. One of the most important factors that governs the success of TME surgery is the relationship of tumour to the circumferential resection margin (CRM). Tumour involves the CRM in up to 20% of patients undergoing TME surgery, and results in both poor survival and local recurrence. It is therefore clear that the importance of the decision regarding the use of pre-operative therapy lies with the relationship of the tumour to the mesorectal fascia. In addition, a high-spatial-resolution MRI technique will identify tumours exhibiting other poor prognostic features, namely, extramural spread >5 mm, extramural venous invasion by tumour, nodal involvement, and peritoneal infiltration. The potential benefits of a selective approach using MRI-based selection criteria are evident. That is, over 50% of patients can be treated successfully with primary surgery alone without significant risk of local recurrence or systemic failure. Of the remainder, potentially dramatic improvements may be achieved through the use of intensive and targeted preoperative therapy aimed not only at reducing the size of the primary tumour and rendering potentially irresectable tumour resectable with tumour-free circumferential margins, but also at enabling patients at high risk of systemic failure to benefit from intensive combined modality therapy aimed at eliminating micrometastatic disease.

Endosonography↗

Effects of ethidium bromide, tetramethylethidium bromide and betaine B on the ultrastructure of HeLa cell mitochondria in situ. A comparative binding study.

Several investigators have described the ultrastructural changes that occur in the mitochondria of cells in tissue cultures after treatment with the drug ethidium bromide (E). The mitochondria swell and the cristae become greatly altered and finally disappear; in the cristae-free region of the matrix electron-dense granules can be observed. It has been assumed that intercalation of E between the base pairs of the mitochondrial DNA induces the formation of the granular inclusions. To investigate whether intercalation is really the initial step in the generation of dense granules inside the matrix, we performed a comparative incubation study of HeLa-cell mitochondria in situ using three closely related dyes (D), i.e., E, tetramethylethidium bromide (TME) and betaine B (B). They strongly differ with regard to their affinity for DNA and their ability to cross membranes. E was used as a reference dye. TME does not intercalate, but is externally bound to DNA only weakly. The neutral B is not bound at all, but can cross membranes more easily than the cation E. Moreover, in aqueous solutions at pH approximately equal to 7.0, B is in equilibrium with its protonated cation BH. BH and E have almost equal affinities for DNA. Therefore B may quickly pass the inner mitochondrial membranes and the cristae, and should then be bound inside the matrix, thus forming a BH-DNA complex. On the assumption that intercalation is necessary for the generation of intramitochondrial electron-dense bodies, we predicted that BH/B should be more efficient than E, while TME should be relatively ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)

Betaine↗

[Identification of pelvic autonomic nerves during partial and total mesorectal excision--influence parameters and significance for neurogenic bladder].

INTRODUCTION: The objective of the present prospective study was to determine the frequency of pelvic autonomic nerve preservation (PANP) during total mesorectal excision (TME) for rectal carcinoma, and to identify a possible link between PANP and postoperative micturition disturbances. METHODS: Between March 1997 and February 2003, 229 patients with adenocarcinoma of the rectum were operated on with sphincter preservation in 178 (78%) cases. In 101 (48%) patients, the tumor did not invade the muscularis propria. To determine influence parameters on the achievement of complete PANP, a multivariate analysis was performed. The number of complete-partial-or nonidentification of the nerves (superior hypogastric plexus up to the neurovascular bundles) was documented and correlated with micturition disturbances. RESULTS: The pelvic autonomic nerves were identified completely in 169 (74%), partially in 25 (11%), and could not be demonstrated in 35 (15%) patients. Multivariate analysis showed multivisceral resection ( p<0.001), gender ( p<0.001), surgeon (<25 operations >, p<0.001), and tumor site (middle/upper third vs lower third of rectum, p= 0.011) to exert an independent influence on the achievement of complete PANP. Twenty (8.8%) patients needed a long-term urinary catheter. Preservation of the parasympathetic nerves was associated with low bladder dysfunction rates (4.1 vs 22.4%, p<0.001). CONCLUSIONS: To minimize the risk of postoperative micturition disturbances due to neurogenic bladder, pelvic autonomic nerves should be identified during TME. Neurogenic bladder after TME is a useful parameter to assess the quality of surgical treatment for rectal carcinoma.

Adult↗

Integrating necroptosis and immune landscapes: a multi-omics-derived NecropImmScore stratifies prognosis and therapy in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) remains the deadliest gynecologic malignancy, largely due to its immunosuppressive tumor microenvironment (TME) and resistance to therapy. Necroptosis, a regulated lytic cell death pathway mediated by the RIPK1-RIPK3-MLKL axis, can trigger immunogenic cell death, but its specific role in shaping the OC immune landscape and its clinical translation potential are posorly understood. METHODS: We employed multi-omics analysis (transcriptomics, genomics, clinical data) from TCGA-OV (n&#x2009;=&#x2009;380), ICGC OV-AU, and IMvigor210 cohorts, combined with rigorous in vitro functional validation using OC cell lines (SKOV3, HEY), macrophages (THP-1 derived), and T cells (Jurkat). Computational immunology approaches (ESTIMATE, CIBERSORT, ssGSEA) quantified immune infiltration. We identified MLKL-associated immune genes, performed survival analysis (Kaplan-Meier, Cox regression), and constructed a necroptosis-immune signature (NecropImmScore) using consensus clustering and PCA of 102 prognostic genes. Drug sensitivity was predicted via pRRophetic and CellMiner. RESULTS: MLKL emerged as a protective prognostic biomarker (p&#x2009;=&#x2009;0.018), significantly correlated with enhanced immune infiltration (ImmuneScore, StromalScore, ESTIMATEScore; p&#x2009;<&#x2009;2.22e-16), M1 macrophage polarization (p&#x2009;=&#x2009;0.006), activated CD4&#x2009;+&#x2009;T cells (p&#x2009;=&#x2009;0.003), and elevated immune checkpoint expression (PD-L1, CTLA4, LAG3, TIGIT). In vitro, MLKL overexpression in OC cells promoted M1 polarization (p&#x2009;<&#x2009;0.05), activated Jurkat T cells (upregulated CCR4/5/7/9, CD69, CD3D/E, GZMB; p&#x2009;<&#x2009;0.05), and induced key chemokines (CXCL9/10/11/13) critical for immune cell recruitment. Integration of MLKL-related and immune-related DEGs (n&#x2009;=&#x2009;632) revealed enrichment in T-cell activation, chemokine signaling, and antigen presentation pathways (FDR&#x2009;<&#x2009;0.05). Consensus clustering based on 102 survival-associated genes defined three molecular subtypes (Clusters A-C) with divergent survival (p&#x2009;=&#x2009;0.019), necroptosis activity, and immune infiltration (Cluster C: best prognosis, highest MLKL/ImmuneScore). The derived NecropImmScore robustly stratified patients: high-score correlated with superior overall survival (TCGA: p&#x2009;<&#x2009;0.001; ICGC: p&#x2009;=&#x2009;0.014), inflamed TME phenotype, elevated checkpoint expression, and improved response to anti-PD-L1 in IMvigor210. Critically, high NecropImmScore predicted higher BRCA1 mutation frequency (AUC&#x2009;=&#x2009;0.802), synergy with BRCA1 status for prognosis, higher homologous recombination deficiency (HRD) score, sensitivity to cisplatin (p&#x2009;=&#x2009;0.014), paclitaxel (p&#x2009;=&#x2009;0.016), gemcitabine (p&#x2009;=&#x2009;0.017), and provided superior prognostic stratification when combined with TMB and HRD score (p&#x2009;<&#x2009;0.001). CONCLUSION: This study establishes MLKL as a master regulator of anti-tumor immunity in OC, driving chemokine-mediated immune cell recruitment and TME reprogramming. The novel NecropImmScore is a multifaceted biomarker that effectively predicts prognosis, immunotherapy response, BRCA1 deficiency, and chemosensitivity, offering significant potential for guiding precision therapeutic strategies in OC.

Humans↗

Laparoscopic versus open total mesorectal excision with anal sphincter preservation for low rectal cancer.

BACKGROUND: The Laparoscopic approach has been applied to colorectal surgery for many years; however, there are only a few reports on laparoscopic low and ultralow anterior resection with construction of coloanal anastomosis. This study compares open versus laparoscopic low and ultralow anterior resections, assesses the feasibility and efficacy of the laparoscopic approach of total mesorectal excision (TME) with anal sphincter preservation (ASP), and analyzes the short-term results of patients with low rectal cancer. METHODS: We analyzed our experience via a prospective, randomized control trail. From June 2001 to September 2002, 171 patients with low rectal cancer underwent TME with ASP, 82 by the laparoscopic procedure and 89 by the open technique. The lowest margin of tumors was below peritoneal reflection and 1.5-8 cm above the dentate line (1.5-4.9 cm in 104 cases and 5-8 cm in 67 cases). The grouping was randomized. RESULTS: Results of operation, postoperative recovery, and short-term oncological follow-up were compared between 82 laparoscopic procedures and 89 controls who underwent open surgery during the same period. In the laparoscopic group, 30 patients in whom low anterior resection was performed had the anastomosis below peritoneal reflection and more than 2 cm above the dentate line, 27 patients in whom ultralow anterior resection was performed had anastomotic height within 2 cm of the dentate line, and 25 patients in whom coloanal anastomosis was performed had the anastomosis at or below the dentate line. In the open group, the numbers were 35, 27, and 27, respectively. There was no statistical difference in operation time, administration of parenteral analgesics, start of food intake, and mortality rate between the two groups. However, blood loss was less, bowel function recovered earlier, and hospitalization time was shorter in the laparoscopic group. CONCLUSION: Totally laparoscopic TME with ASP is feasible, and it is a minimally invasive technique with the benefits of much less blood loss during operation, earlier return of bowel function, and shorter hospitalization.

Adult↗

Aging reversibility: from thymus graft to vegetable extract treatment-- application to cure an age-associated pathology.

Neonatal thymus graft and thymus calf extract (TME) in vivo treatment exert similar corrective actions on different mouse age-related alterations. The aim of the present paper is to investigate whether a vegetal extract, wheat sprout extract (WESPRE), could mimic the thymus action on recovering age-related alterations and if this extract can cure an age-associated pathology, the cataract in dogs. Present experiments were carried out by using WESPRE and TME in vivo in old mice to check their ability to recover the altered DNA synthesis in hepatocyte primary cultures. Old mice treated with WESPRE and TME showed a recovery of hepatocyte DNA synthesis levels when compared with the old untreated ones. The increase of DNA and protein contents observed in aged animals is reduced by WESPRE treatments to levels observed in young mice hepatocytes. We measured also WESPRE phosphorylation activity by endogenous kinase: it was from 10 to 40 times higher with respect to wheat seeds. Old dogs were orally treated for a month and the lens opacity analysed before and after the treatment. Results showed a reduction from 25 to 40% of lens opacity. The efficacy of wheat sprouts in the recovery of age-related alterations and in treating age-associated pathologies could be due to the contemporary presence of small regulatory acid peptides, a remarkable level of highly energetic phosphoric radicals and antioxidant molecules, peculiarities that may be, to some extent, related to the aging process regulation.

Animals↗

Purification of 125I-labeled succinyl cyclic nucleotide tyrosine methyl esters by high-performance liquid chromatography.

Carrier free 125I-labeled succinyl cyclic adenosine monophosphate (ScAMP) and succinyl cyclic guanosine monophosphate (ScGMP) tyrosine methyl esters (TME) were purified by reversed phase high-performance liquid chromatography (HPLC) or descending paper chromatography. Using an isocratic buffer for HPLC, mono-ScAMP-125I-TME and mono-ScGMP-125I-TME were eluted from a C18 column at 8.9 and 6.9 min, respectively. Both of the mono-iodinated radioligands were completely separated from their noniodinated precursors and other iodinated products. The radioligands purified by HPLC or paper chromatography were used for the radioimmunoassay (RIA) of cAMP and cGMP. Cyclic AMP or cGMP inhibited binding of the HPLC purified radioligands at three- to fivefold lower concentrations than the paper chromatography purified radioligands. The sensitivity of the RIA decreased with time if paper chromatography purified radioligands were used, but remained stable for 4 months if the HPLC purified compounds were used, even with storage at 4 degrees C. We attribute these results to better purification of radioligands by the HPLC than by the paper chromatography. Using optimal conditions the HPLC method takes only 10 min and results in a high yield (greater than 95%) of added 125I into the monoiodinated products.

Chromatography, High Pressure Liquid↗

Tcp-1 gene is not responsible for the maternal lethality effect of Thp mutation in mice.

Embryos receiving either the Thp or the twLub2 mutation from their mother die during gestation. In contrast, heterozygous embryos receiving the mutant chromosome from the father are completely viable. In both Thp and twLub2 mutants, one chromosome 17 carries a deletion, which suggests the existence of a discrete maternal lethality effect locus (Tme). In the region whose deletion is responsible for the Thp or twLub2 mutation, a single gene has been cloned so far, the Tcp-1 gene. In the present study, we examined the expression of Tcp-1 gene in mutant embryos carrying either a maternal or a paternal Thp chromosome to test whether this gene could be involved in the Tme effect. We found that the levels of Tcp-1-specific transcripts were similar in both mutant embryos from reciprocal crosses and corresponded to half the levels found in the normal littermates. In addition, the paternal and maternal Tcp-1 alleles had identical methylation patterns. These results indicate that Tcp-1 is not responsible for the maternal lethality effect, and therefore is not located at the Tme locus.

Animals↗

Electron-microscopic appearance of the DA virus, a demyelinating murine virus.

The DA virus is a neurotropic murine virus which can induce acute encephalomyelitis in suckling mice and a chronic myelopathy in weanlings. The agent has been attenuated by serial passage in baby hamster kidney (BHK-21) cells. When attenuated virus is inoculated in 8-week-old C3HeJ mice a myelopathy of delayed onset with prominent demyelination of lateral and anterior columns occurs. The DA virus is believed to be related to the Theiler murine encephalomyelitis (TME) viruses because of the similar clinical and pathological conditions which it causes, and because neutralization tests indicate shared antigens between it and GD7, a TME virus. This paper reports electron-microscopic studies of BHK-21 cells infected with DA virus. The cells were prepared 24 and 48 hr after inoculation. Cytopathic effects were observed and infected cells contained plaques consisting of numerous 25 nm virus particles in crystalline array. The virions were exclusively intracytoplasmic and were morphologically indistinguishable from human poliomyelitis virus. These observations appear to establish DA as a picorna virus, related to the TME virus group. The chronic myelopathy caused by DA may prove relevant to chronic demyelinative myelopathies in man, such as multiple sclerosis, and also to amyotrophic lateral sclerosis.

Animals↗

Mesorectal excision for rectal cancer.

Concern about world wide local recurrence rates for rectal cancer of 20-45%, together with anxiety at the recent proliferation of adjuvant therapies, led us to review the efficacy of total mesorectal excision (TME) with which no adjuvant therapy had been combined. Precise, sharp dissection is undertaken around the integral mesentery of the hind gut, which envelopes the entire mid rectum. This procedure adds to operative time and complications but has been claimed to eliminate virtually all locally recurrent disease after "curative" surgery. Independent analysis (J. K. M.) of prospective follow-up data extended over a 13-year interval (1978-91; mean 7.5 years). The actuarial local recurrence rate after curative anterior resection at 5 years is 4% (95% Cl 0-7.5%) and the overall recurrence rate is 18% (10-25%). 10-year figures are 4% (0-11%) and 19% (7-32%). In view of the high-risk classification used for the North Central Cancer Treatment Group (NCCTG), which has led to a trend to chemoradiotherapy, a similar group of high-risk Basingstoke cases was constructed for comparison purposes. This group included 135 consecutive Dukes' B (B2) and Dukes' C cancer operations, both anterior resection and abdominal-perineal excision, for tumours below 12 cm from the anal verge. Results from TME alone are substantially superior to the best reported (NCCTG) from conventional surgery plus radiotherapy or combination chemoradiotherapy: 5% local recurrence at 5 years compared with 25% and 13.5%, respectively; and 22% overall recurrence compared with 62.7% and 41.5%, respectively (Dukes' B cases [B2], 15%; Dukes' C cases, 32%). Meticulous TME, which encompasses the whole field of tumour spread, can improve cure rates and reduce the variability of outcomes between surgeons. Far more genuine "cures" of rectal cancer are possible by surgery alone than have generally been believed or are currently accepted. Better surgical results are an essential background for the more selective use of adjuvant therapy in the future.

Aged↗

Temporal correspondence of intracranial, cochlear and scalp-recorded human auditory nerve action potentials.

Conventional, vertex-ipsilateral ear records ('A'), as well as 3-channel Lissajous' trajectories (3-CLTs) of auditory brain-stem evoked potentials (ABEPs) were recorded from the scalp simultaneously with tympanic membrane electrocochleograms ('TME') and auditory nerve compound action potentials ('8-AP') recorded intracranially using a wick electrode on the auditory nerve between the internal auditory meatus and the brain-stem. The recordings were made during surgical procedures exposing the auditory nerve. The peak latency recorded from 'TME' corresponded to trajectory amplitude peak 'a' of 3-CLT and to peak 'I' of the 'A' channel ABEP. Peak latency of '8-AP' was slightly longer than the latency of peak 'II' of 'A' when '8-AP' was recorded from the root entry zone and the same or shorter when recorded from the nerve trunk. '8-AP' peak latency was shorter than trajectory amplitude peak 'b' of 3-CLT regardless of where the wick electrode was along the nerve. Peak latencies from all recording sites clustered into two distinct groups--those that included N1 from 'TME,' peak 'I' of the 'A' record and trajectory amplitude peak 'a' of 3-CLT, and those that included the negative peak of '8-AP' and trajectory amplitude peak 'b' of 3-CLT, as well as peak 'II' of the 'A' record, when present. In one case, the latency of peak 'II' and trajectory amplitude peak 'b' was manipulated by changing the conductive properties of the medium surrounding the auditory nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗

Cholinoceptor-mediated mechanical and electrical responses of rat oesophageal striated musculature. A comparison of two in vitro methods.

1. Both muscarinic and nicotinic cholinoceptor agonists produce a contractile response of the rat oesophageal tunica muscularis externa (TME) in vitro. 2. The muscarinic receptor-mediated responses were confined to the distal 0.5 cm of the TME, which contains an admixture of smooth muscle. 3. Nicotinic receptor-mediated responses were obtained throughout the length of the TME striated musculature and consisted of a fast and slow component, representing TTX-sensitive contractions, associated with muscle action potentials, and electrically silent contractures, respectively. 4. Contractions were observed only in superfused preparations. 5. Contractures were resistant to changes in extracellular cation concentrations designed to eliminate generation of nerve and muscle action potentials or release of neurotransmitters.

Animals↗

Thermal marrow expansion: effect of temperature on bone marrow distribution.

The distribution of bone marrow in adult mammals is limited mainly to those bones deeply embedded in the body and subject to the higher core body temperature. Active marrow is much less prevalent in the limbs. In the past this was attributed to the lower temperature of the peripheral bone marrow. We have studied the possibility of stimulating hematopoiesis in the limbs (and tails) by increasing the limb temperature. This has been done by elevating the ambient temperature of mice and by tail implantation techniques. Mice incubated at ambient temperature of 22 degrees C can be "expanded" to have markedly enhanced marrow activity in the limbs by either incubation for seven days or more at 34 degrees C, or by implantation of the bone into core temperature areas (peritoneal implantation). The increase in marrow activity is shown both histologically and by 59Fe uptake techniques. Anemia does not enhance this effect, indicating a local phenomenon. A variety of experiments suggest that temperature per se and not temperature-induced increase in blood flow is involved. The increase in marrow activity is accompanied by a modest local increase in clonogenic marrow stem cells but it cannot be shown for certainty whether the phenomenon of Thermal Marrow Expansion (TME) is due to the local effect of elevated temperature on stem or stromal cells. The erythrocytes produced by TME appear normal by in vivo fragility testing. TME may have clinical usefulness in man if the phenomenon occurs in the same fashion as rodents.

Anemia↗

Single-cell and spatial transcriptomic technologies for lung cancer tumor microenvironment analysis.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide; beyond its rising incidence, its marked molecular heterogeneity and complex tumor microenvironment (TME) hinder treatment response and drive resistance, contributing directly to its high mortality rate. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) provide complementary approaches for dissecting these features. scRNA-seq enables high-resolution analysis of cellular diversity and transcriptional states but requires tissue dissociation and therefore loses spatial context. In contrast, ST preserves tissue architecture and provides insights into how gene-expression programs within the TME are organized, although no currently available spatial platform combines whole-transcriptome coverage with true single-cell resolution over large tissue areas. Together, these technologies have enabled detailed mapping of tumor, immune and stromal populations and of their spatial interactions, revealing functionally distinct cellular niches that contribute to immune evasion, metastasis and response to therapy. In this narrative review we organize the primary literature around a single question, how spatially structured cellular ecosystems, rather than individual cell types, determine therapeutic response and resistance in lung cancer - and we explicitly separate observations that are reproducible across independent cohorts and platforms from those that remain confined to single studies. We further summarize the technical, analytical and logistic barriers that currently prevent spatially resolved signatures from entering routine diagnostic pathology. Understanding dysregulated pathways and spatially constrained intercellular communication within the TME helps identify candidate biomarkers and may support the identification of therapeutic approaches directed at tumor-intrinsic programs as well as at microenvironment-driven resistance mechanisms.

Cell-cell communication↗

MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma.

Immune checkpoint inhibitors show insufficient efficacy against pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) has a remarkable influence on responsiveness to cancer immunotherapy. The aim of this study was to investigate immunosuppressive characteristics of TME in PDAC tissues. The flow cytometry (FCM) of PDAC surgical specimens revealed that the profile of tumor-infiltrating leukocytes was classified into myeloid cell- and T-cell-dominant subtypes; the myeloid subtype was associated with poorer patient outcomes. Myeloid-derived suppressor cells (MDSCs) showed the highest hazard ratio among various myeloid cell types. Single-cell RNA sequencing and FCM revealed that most MDSCs, but not lymphocytes, in PDAC tissues characteristically express CD74. Macrophage migration inhibitory factor (MIF), a CD74 ligand, was highly expressed in cancer-associated fibroblasts (CAFs) and cancer cells. Spatial transcriptomics demonstrated that the MIF-CD74+ myeloid cell interaction was recognized in CAF-dominant areas in PDAC tissue. CAFs expressing immune suppressor molecules such as MFAP5 and LRRC15 were consistent with MIF+ CAFs. Furthermore, MIF+ CAFs enhanced the migratory activity of MDSCs and promoted MDSC induction and activation. In the murine model, MDSCs were significantly increased in MIF-expressing PDAC tumors, as were CD74+ M-MDSCs per M-MDSC, confirming in vivo interaction between CD74 and MIF. MDSCs play a crucial role in creating an immunosuppressive TME in PDAC; the MIF-CD74 axis drives interactions between MDSCs and CAFs.

Humans↗

An immune exhaustion signature predicts prognosis and identifies patients with diffuse large B-cell lymphoma (DLBCL) who derive preferential benefit from chimeric antigen receptor (CAR)-T cell therapy.

BACKGROUND: The tumor microenvironment (TME) is a key determinant of prognosis in diffuse large B-cell lymphoma (DLBCL). While T-cell exhaustion is implicated in therapeutic failure, its precise molecular hallmarks and utility for predicting response to modern immunotherapies, such as chimeric antigen receptor (CAR)-T cell therapy, remain unclear. METHODS: We performed an integrative analysis of transcriptomic and clinical data from multiple DLBCL cohorts (The Cancer Genome Atlas [TCGA], GSE181063, GSE10846, GSE248835, GSE182434). We used unsupervised clustering, exploratory analysis of single-cell RNA sequencing data, and the least absolute shrinkage and selection operator for variable selection (LASSO-Cox) regression to characterize the exhausted TME, construct a prognostic model, and evaluate its predictive value for CAR-T cell therapy. The model's dynamic behavior was assessed in a proof-of-concept longitudinal cohort of patients treated with the T-cell-engaging bispecific antibody glofitamab. RESULTS: We identified a "high-exhaustion" subtype associated with significantly poorer overall survival (OS; log-rank P = 0.016). Based on this, we developed a five-gene immune exhaustion-Related Prognostic Score (IERPS) that served as a robust independent predictor of poor OS across multiple cohorts. Critically, in a cohort of 256 relapsed/refractory patients, the IERPS was strongly prognostic for event-free survival (EFS) in the standard-of-care (SOC) arm (HR = 2.02, 95% confidence interval [95% CI]: 1.07-3.81, P = 0.029) but lost prognostic significance in the CAR-T arm (HR = 0.70, 95 % CI: 0.35-1.40, P = 0.314). This significant interaction suggests that CAR-T cell therapy may abrogate the poor prognosis associated with a high IERPS. Biologically, exploratory single-cell analysis (n = 4 samples) defined the high-IERPS state by hallmarks of classical T-cell exhaustion, and a descriptive case study showed the score dynamically tracked clinical response to glofitamab. CONCLUSIONS: A state of active T-cell exhaustion and a suppressive TME drive the adverse immune phenotype in DLBCL. Our IERPS model captures this dysfunctional state, acting as a powerful prognostic tool and, more importantly, as a potential predictive biomarker to identify high-risk patients who appear to overcome their inherently poor prognosis through CAR-T cell therapy.

Biomarkers↗

Beyond oncogenesis: The emerging role of EZH2 in tumor microenvironment.

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and the catalytic component of Polycomb Repressive Complex 2, facilitates epigenetic modifications via the repressive H3K27me3 mark, consequently modulating the expression of numerous genes implicated in cellular proliferation and survival. Overexpression or dysregulation of EZH2 has been observed extensively across several malignancies, where it plays a major role in shaping the tumor microenvironment, promoting angiogenesis, cytokine secretion, and matrix remodeling. EZH2 mediates immune evasion, particularly in response to immunotherapy and checkpoint blockade. These interactions also position EZH2 as a key mediator of therapy resistance to chemotherapy, immunotherapy, and targeted therapy. Consequently, a comprehensive understanding of EZH2's function and its interactions within the TME and during cancer progression is crucial. This review aims to enhance the current understanding of EZH2 and its roles in the TME, cancer development, and therapeutic responses. This review will discuss the canonical and non-canonical functions of EZH2, summarize its established and evolving roles in cancer and the TME, and highlight its effects on tumor immunity and therapeutic efficacy.

Humans↗

Differentiation of subendocardial and transmural infarction using two-dimensional strain rate imaging to assess short-axis and long-axis myocardial function.

OBJECTIVES: This study sought to differentiate the transmural extent of infarction (TME) by assessment of the short-axis and long-axis function of the left ventricle (LV) using 2-dimensional (2D) strain. BACKGROUND: The differentiation of subendocardial infarction from transmural infarction has significant prognostic and clinical implications. METHODS: Contrast-enhanced magnetic resonance imaging (CE-MRI) and dobutamine stress echocardiography (DBE) were performed in 80 patients (age 63 +/- 10 years) with chronic ischemic LV dysfunction. Myocardial function was assessed in the short axis at the midventricular level using peak strain rate (SR) and strain (S) in circumferential and radial dimensions, and was assessed in the long axis using longitudinal SR and S. Wall motion analysis was performed during DBE to assess for contractile reserve. RESULTS: Transmural infarct segments had lower circumferential S (-10.7 +/- 6.3) and SR (-1.0 +/- 0.4) than subendocardial infarcts (S: -15.4 +/- 7.0, p < 0.0001; SR: -1.4 +/- 0.8, p = 0.02) and normal myocardium (S: p < 0.0001; SR: p < 0.0001). Transmural and subendocardial infarct segments had similar radial S and SR. Subendocardial infarct segments showed significant reduction of longitudinal S (-13.2 +/- 5.6) and SR (-0.91 +/- 0.45) compared with normal myocardium (S: -17.8 +/- 5.4, p < 0.0001; SR: -1.1 +/- 0.41, p < 0.0001), but there were no significant differences between subendocardial and transmural infarct segments (p = 0.09). Wall motion analysis by DBE could not identify subendocardial infarction on CE-MRI (TME 1% to 50%: DBE scar 38%, DBE viable 38%, DBE ischemic 24%, p = NS). CONCLUSIONS: The combined assessment of long-axis and short-axis function using 2D strain may be used to identify TME.

Aged↗