[Tanshinone reverses androgen deprivation-induced invasion of prostate cancer cells by suppressing PI3K and AKT signaling pathways].

OBJECTIVE: To explore the effect of tanshinone on the invasion of PCa cells induced by androgen-deprivation therapy (ADT) and its possible action mechanism. METHODS: We treated human PCa LNCaP cells with tanshinone at 0 nmol/L (the control group), 5 nmol/L (tanshinone group 1), 10 nmol/L (tanshinone group 2) and 20 nmol/L (tanshinone group 3), respectively. Then we detected their cloning, angiogenesis and invasion abilities by plate cloning assay, tube-formation assay and Transwell chamber assay, respectively, examined their apoptosis using the AnnexinV-FITC/PI double staining method, and determined the protein expressions of phosphatidylinositol 3-kinase (PI3K), p-PI3K, protein kinase B (AKT) and p-AKT by Western blot. RESULTS: Compared with the control group, the PCa LNCaP cells in the tanshinone groups 1, 2 and 3 showed significant dose-dependent decreases in the clone formation rate (ï¼»25.14 ± 5.19ï¼½% vs ï¼»19.33 ± 4.12ï¼½% vs ï¼»14.69 ± 4.71ï¼½% vs ï¼»9.35 ± 2.37ï¼½%, P<0.05), number of cellular lumens (ï¼»23.20 ± 4.85ï¼½ vs ï¼»19.80 ± 5.12ï¼½ vs ï¼»14.40 ± 4.16ï¼½ vs ï¼»10.20 ± 3.21ï¼½ per microscopic field, P<0.05) and count of transmembrane cells (ï¼»62.80 ± 8.97ï¼½ vs ï¼»50.40 ± 7.62ï¼½ vs ï¼»38.60 ± 5.16ï¼½ vs ï¼»27.40 ± 4.91ï¼½ per microscopic field, P<0.05), increase in the rate of cell apoptosis (ï¼»3.58 ± 0.74ï¼½% vs ï¼»8.97 ± 1.36ï¼½% vs ï¼»14.64 ± 4.10ï¼½% vs ï¼»21.17 ± 5.37ï¼½%, P<0.05), and down-regulation of the expressions of p-PI3K, PI3K, p-AKT and AKT (P<0.05). CONCLUSION: Tanshinone can reverse ADT-induced invasion of PCa cells, reduce their clone formation and angiogenesis, promote their apoptosis, and inhibit the activity of PI3K and AKT signaling pathways.

Evaluating the efficacy of standardized pressure ulcer management protocols in the prevention of pressure injuries among patients undergoing neurosurgical procedures.

Pressure injuries are a significant concern for patients undergoing neurosurgical procedures due to prolonged immobility and the complexity of care. This study evaluates the efficacy of standardized pressure ulcer management protocols in preventing pressure injuries and enhancing patient care in a neurosurgical context. A comprehensive retrospective analysis was conducted at a single institution from December 2020 to December 2023, comparing 50 patients who received standardized pressure ulcer management (intervention group) with 50 patients who received conventional care (control group). The study assessed the incidence of pressure ulcers, patient comfort levels using the Kolcaba Comfort Scale and sleep quality using the Richards-Campbell Sleep Questionnaire (RCSQ). Statistical analysis was performed using SPSS software, version 27.0, applying t-tests and chi-square tests as appropriate. The intervention group exhibited a significantly lower incidence of pressure ulcers at all measured time points post-surgery compared to the control group. Patient comfort levels in the intervention group were consistently higher across psychological, environmental, physiological and socio-cultural domains. Sleep quality metrics, including sleep depth, latency to sleep onset and overall sleep quality, were significantly improved in the intervention group. The implementation of standardized pressure ulcer management protocols in neurosurgical care significantly reduces the incidence of pressure injuries, enhances patient comfort and improves sleep quality. These findings highlight the importance of adopting structured care protocols to improve postoperative outcomes and patient well-being in neurosurgical settings.

An uncommon and easily overlooked case: Delayed intraperitoneal bladder rupture following blunt trauma: A case report and review of the literature.

INTRODUCTION: Delayed intraperitoneal bladder rupture is a rare clinical occurrence, frequently overlooked and misdiagnosed due to its nonspecific clinical manifestations. However, literature provides only a limited number of cases reporting delayed intraperitoneal bladder rupture resulting from blunt abdominal injury. PATIENT CONCERNS: A 72-year-old female pedestrian was struck by a vehicle and experienced sudden, severe abdominal pain on the 8th day following the injury. Abdominal B-ultrasound revealed a significant accumulation of peritoneal effusion. The abdominal puncture retrieved serosanguinous ascites. Then the patient was promptly transferred to our hospital. Upon transfer, the physical examination revealed the patient vital signs to be stable, accompanied by mild abdominal distension, slight tenderness, tension, and an absence of rebound tenderness. Urinalysis detected microscopic hematuria, while contrast-enhanced computed tomography (CT) revealed considerable fluid accumulation in the abdominal cavity, without evidence of solid organ damage, and the bladder was adequately filled. DIAGNOSIS: The diagnosis of delayed intraperitoneal bladder rupture primarily relied on intraoperative observations. INTERVENTIONS: An emergency exploratory laparotomy was performed, revealing a linear rupture at the dome of the bladder. Subsequently, the bladder rupture was repaired. OUTCOMES: Postoperative cystography demonstrated full recovery and the patient was discharged 28 days post-surgery. The postoperative recovery was uneventful without any complications. CONCLUSIONS: A well-distended bladder observed in CT does not definitively rule out the potential for bladder injury. False negatives may occur due to incomplete bladder filling during CT cystography. Retrograde cystography can identify cases missed by CT cystography. In cases of substantial intra-abdominal free fluid, surgical intervention should be actively considered for patients with blunt abdominal trauma without concurrent solid organ damage.

The SMAC mimetic birinapant alleviates lipopolysaccharide-induced acute lung injury by inhibiting MAPK signaling.

The second mitochondria-derived activator of caspases (SMAC) mimetic birinapant attenuated liver injury by inhibited the degradation of tumor necrosis factor receptor-associated factor 3 (TRAF3) and activation of mitogen-activated protein kinase (MAPK) signaling pathway in liver macrophage, but its role in LPS induced acute lung injury (ALI) is not understood. The present study was to investigate the effects of birinapant on ALI and its possible mechanism. A dose of birinapant (30 mg/kg) or a vehicle was administered intravenously 24 hours before LPS (100 µg) stimulation in mice. The levels of TNF-α, IL-6 and IL-1ß in bronchoalveolar lavage fluid (BALF) were measured by ELISA. The infiltrated macrophages and expression of monocyte chemoattractant protein-1 (MCP-1) was determined by immunohistochemistry staining in the lung tissues. The JNK and p38 MAPK activation, protein expression and K48-linked polyubiquitination of TRAF3 were determined in alveolar macrophage cell line (MH-S cells) after 1µg/ml LPS stimulation. The results showed that the birinapant down-regulated the levels of TNF-α, IL-6 and IL-1ß in the BALF. In addition, birinapant markedly inhibited macrophages infiltration and MCP-1 protein expression in lung tissues. At last, birinapant suppressed the MAPKsignaling pathway and K48-linked ubiquitinated degradation of TRAF3 in MH-S cells after LPS administration. In conclusion, the results proved that birinapant protected against LPS-induced ALI through inhibiting MAPK activation and K48-linked ubiquitination of TRAF3 in alveolar macrophages.

Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma.

PURPOSE: Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non-germinal center B-cell-like subset. METHODS: We enrolled 60 patients with newly diagnosed non-germinal center B-cell-like DLBCL in this investigator-initiated, single-arm phase II trial of rituximab, lenalidomide, and ibrutinib (RLI) with the sequential addition of chemotherapy (ClinicalTrials.gov identifier: NCT02636322). Patients were treated with rituximab 375 mg/m2 intravenous once on day 1, lenalidomide 25 mg once per day on days 1-10, and ibrutinib 560 mg once daily continuously of each 21-day cycle (RLI). After two cycles, standard chemotherapy was added to RLI for six additional cycles. The primary end points were overall response rate (ORR) after two cycles of RLI alone and complete response rate after completion of RLI with chemotherapy. In evaluable samples, circulating tumor DNA and DLBCL90 assays were performed. RESULTS: The median age was 63.5 years (range, 29-83 years) with 28% age 70 years or older. The revised international prognostic index identified 42% as high risk, and 62% were double expressor of MYC and BCL2 protein. The ORR after two cycles of RLI was 86.2%, and the complete response rate at the end of RLI-chemotherapy was 94.5%. With a median follow-up of 31 months, the progression-free survival and overall survival were at 91.3% and 96.6% at 2 years, respectively. CONCLUSION: Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high ORR, and RLI with chemotherapy resulted in durable responses. This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.

Non-ribosomal peptide biosynthetic potential of the nematode symbiont Photorhabdus.

Photorhabdus, the symbiotic bacteria of Heterorhabditis nematodes, has been reported to possess many non-ribosomal peptide synthetase (NRPS) biosynthesis gene clusters (BGCs). To provide an in-depth assessment of the non-ribosomal peptide biosynthetic potential of Photorhabdus, we compared the distribution of BGCs in 81 Photorhabdus strains, confirming the predominant presence (44.80%) of NRPS BGCs in Photorhabdus. All 990 NRPS BGCs were clustered into 275 gene cluster families (GCFs) and only 13 GCFs could be annotated with known BGCs, suggesting their great diversity and novelty. These NRPS BGCs encoded 351 novel peptides containing more than four amino acids, and 173 of them showed high sequence similarity to known BGCs encoding bioactive peptides, implying the promising potential of Photorhabdus to produce valuable peptides. Sequence similarity networking of adenylation (A-) domains suggested that the substrate specificity of A-domains was not directly correlated with the sequence similarity. The molecular similarity network of predicted metabolite scaffolds of NRPS BGCs and reported peptides from Photorhabdus and a relevant database demonstrated that the non-ribosomal peptide biosynthetic potential of Photorhabdus was largely untapped and revealed the core peptides deserving intensive studies. Our present study provides valuable information for the targeted discovery of novel non-ribosomal peptides from Photorhabdus.

Enhanced Glioblastoma Selectivity of Harmine via the Albumin Carrier.

Glioblastoma, the most common tumor in the brain, has witnessed very little clinical progress over the last decades. Exploring and discovering new therapeutic strategies for glioblastoma has become a critical problem. Harmine (HM), belonging to the beta-carboline alkaloid, is a natural product and isolated from the seeds of Peganum harmala L., which own notable antitumor activity in vitro. However, the poor water solubility and less selectivity of HM severely limit its clinical use. For enhancing its selective ability to tumor cells, we fabricated a kind of protein nanoparticles (BSA-HM NPs), composed of the modified bovine serum albumin (BSA) and HM. It was substantiated through in vitro and in vivo experiment that BSA-HM NPs could predominantly accumulate in tumor tissues and exhibited remarkably enhanced antitumor efficacy. This study provides a promising strategy to improve the bioavailability and avoid side effects of HM as antitumor agents by choosing BSA as carriers.

Follicular Lymphoma Microenvironment Characteristics Associated with Tumor Cell Mutations and MHC Class II Expression.

Follicular lymphoma (FL) is a B-cell malignancy with a complex tumor microenvironment that is rich in nonmalignant immune cells. We applied single-cell RNA sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T cells, including a cytotoxic CD4 T-cell population. We characterized four major FL subtypes with differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced MHC expression on FL cells. In turn, expression of MHCII genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics of T cells. This provides a classification framework of the FL microenvironment in association with FL genotypes and MHC expression, and informs different potential immunotherapeutic strategies based upon tumor cell MHCII expression. SIGNIFICANCE: We have characterized the FL-infiltrating T cells, identified cytotoxic CD4 T cells as an important component that is associated with tumor cell-intrinsic characteristics, and identified sets of targetable immune checkpoints on T cells that differed from FLs with normal versus low MHC expression. See related commentary by Melnick, p. 374. This article is highlighted in the In This Issue feature, p. 369.

Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma.

PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%), and pancreatitis (3%). Low-grade immune-related AEs were reported in 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune-related AEs occurred in 13% of the patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. The overall response rate (primary end point) was 67%, and the complete response (CR) rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% confidence interval, 8.2-27.6), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow-up of 35 months. The presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a CR and improved PFS. In this single-arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov as #NCT02446457.

Detecting Förster resonance energy transfer in living cells by conventional and spectral flow cytometry.

Assays based on Förster resonance energy transfer (FRET) can be used to study many processes in cell biology. Although this is most often done with microscopy for fluorescence detection, we report two ways to measure FRET in living cells by flow cytometry. Using a conventional flow cytometer and the "3-cube method" for intensity-based calculation of FRET efficiency, we measured the enzymatic activity of specific kinases in cells expressing a genetically-encoded reporter. For both AKT and protein kinase A, the method measured kinase activity in time-course, dose-response, and kinetic assays. Using the Cytek Aurora spectral flow cytometer, which applies linear unmixing to emission measured in multiple wavelength ranges, FRET from the same reporters was measured with greater single-cell precision, in real time and in the presence of other fluorophores. Results from gene-knockout studies suggested that spectral flow cytometry might enable the sorting of cells on the basis of FRET. The methods we present provide convenient and flexible options for using FRET with flow cytometry in studies of cell biology.

Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma.

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML.

Eukaryotic initiation factor 4A (eIF4A), the enzymatic core of the eIF4F complex essential for translation initiation, plays a key role in the oncogenic reprogramming of protein synthesis, and thus is a putative therapeutic target in cancer. As important component of its anticancer activity, inhibition of translation initiation can alleviate oncogenic activation of HSF1, a stress-inducible transcription factor that enables cancer cell growth and survival. Here, we show that primary acute myeloid leukemia (AML) cells exhibit the highest transcript levels of eIF4A1 compared to other cancer types. eIF4A inhibition by the potent and specific compound rohinitib (RHT) inactivated HSF1 in these cells, and exerted pronounced in vitro and in vivo anti-leukemia effects against progenitor and leukemia-initiating cells, especially those with FLT3-internal tandem duplication (ITD). In addition to its own anti-leukemic activity, genetic knockdown of HSF1 also sensitized FLT3-mutant AML cells to clinical FLT3 inhibitors, and this synergy was conserved in FLT3 double-mutant cells carrying both ITD and tyrosine kinase domain mutations. Consistently, the combination of RHT and FLT3 inhibitors was highly synergistic in primary FLT3-mutated AML cells. Our results provide a novel therapeutic rationale for co-targeting eIF4A and FLT3 to address the clinical challenge of treating FLT3-mutant AML.

Novel CD37, Humanized CD37 and Bi-Specific Humanized CD37-CD19 CAR-T Cells Specifically Target Lymphoma.

CD19 and CD37 proteins are highly expressed in B-cell lymphoma and have been successfully targeted with different monotherapies, including chimeric antigen receptor (CAR)-T cell therapy. The goal of this study was to target lymphoma with novel CD37, humanized CD37, and bi-specific humanized CD37-CD19 CAR-T cells. A novel mouse monoclonal anti-human CD37 antibody (clone 2B8D12F2D4) was generated with high binding affinity for CD37 antigen (KD = 1.6 nM). The CD37 antibody specifically recognized cell surface CD37 protein in lymphoma cells and not in multiple myeloma or other types of cancer. The mouse and humanized CD37-CAR-T cells specifically killed Raji and CHO-CD37 cells and secreted IFN-gamma. In addition, we generated bi-specific humanized hCD37-CD19 CAR-T cells that specifically killed Raji cells, CHO-CD37, and Hela-CD19 cells and did not kill control CHO or Hela cells. Moreover, the hCD37-CD19 CAR-T cells secreted IFN-gamma against CD37-positive and CD19-positive target CHO-CD37, Hela-CD19 cells, respectively, but not against CD19 and CD37-negative parental cell line. The bi-specific hCD37-CD19 significantly inhibited Raji xenograft tumor growth and prolonged mouse survival in NOD scid gamma mouse (NSG) mouse model. This study demonstrates that novel humanized CD37 and humanized CD37-CD19 CAR-T cells specifically targeted either CD37 positive or CD37 and CD19-positive cells and provides a basis for future clinical studies.

Selenium-enriched Lactobacillus plantarum improves the antioxidant activity and flavor properties of fermented Pleurotus eryngii.

The effects of selenium (Se) addition methods on antioxidant activity and flavor properties of fermented Pleurotus eryngii (P. eryngii) using Lactobacillus plantarum (L. plantarum) inoculated and natural fermentation were investigated. After fermentation, the Se-enrichment rates in fruiting bodies of Se-added fermented P. eryngii were all more than 50%. Se addition, especially in the form of Se-enriched L. plantarum inoculation, had a significantly positive effect on total phenolic content and DPPH radical scavenging activity. Non-volatiles analysis revealed that the highest ration of lactic acid to acetic acid and the highest umami intensity were observed in P. eryngii fermented by inoculating Se-enriched L. plantarum (Lp-Se). Principal components analysis and cluster analysis of volatiles clearly separated Se-treated and plain experiments, which mainly due to dissimilarities in alcohols, aldehydes and ketones. Additionally, Lp-Se obtained the highest alcohols, especially 1-octen-3-ol with mushroom flavor. In short, Se-enriched L. plantarum inoculation could produce high-quality fermented P. eryngii.

Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas.

Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10-149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma.

CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6-HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II-dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas. SIGNIFICANCE: We have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP-mutant cells in tandem with promoting antitumor immunity.This article is highlighted in the In This Issue feature, p. 327.

The applications of metabolomics in the molecular diagnostics of cancer.

Introduction: Metabolomics, the study of metabolites, is a promising research field for cancers. The metabolic pathway in a tumor cell is different from a normal tissue cell. There are two approaches to study the metabolism, targeted and untargeted. The general approach is that metabolomic data are interpreted by bioinformatics tools correlating with metabolomic databases to obtain significant findings. With the use of specific analysis tools, such as nuclear magnetic resonance (NMR) and mass spectrometer (MS) combined with chromatography, metabolic profile or metabolic fingerprint of various biological specimens could be obtained. The applications of metabolomics are used to discover potential cancer biomarkers and monitor the metastatic state, therapeutic and drug response for better patient management. Areas covered: In this review, the author introduce metabolomics and discuss the use of metabolomics approaches in different cancers, including the study of colorectal cancer, prostate cancer, liver cancer, pancreatic cancer and breast cancer using NMR and MS. Expert opinion: Knowledge on the molecular basis of cancer metabolism and its potential clinical applications has been improving recently. However, there are still many challenges for the technological development and integration of metabolomics with other omics spaces such as genomics. In the near future, it is expected that metabolomics will play an important role in cancer molecular diagnostics.

Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma.

The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin µ (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysis-targeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.

Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.

The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.

Prediction of Hidden Blood Loss During Posterior Spinal Surgery.

Objective Identification of the risk factors for extraordinary hidden blood loss (HBL) could clarify the underlying causes and provide more appropriate management. This study aims to identify the predictors of HBL in spinal surgery.Methods Medical records were retrospectively retrieved to collect the data of patients who undergoing posterior thoracic and lumbar fusion surgery or scoliosis surgery. Demographic information, perioperative visible blood loss volume, as well as laboratory results were recorded. The patients receiving fusion surgery or scoliosis surgery were further divided into the HBL positive subgroup and the HBL negative subgroup. Differences in the variables between the groups were then analyzed. Binary logistic regression analysis was performed to determine independent risk factors associated with HBL.Results For patients undergoing posterior spinal surgery, the independent risk factors associated with HBL were autologous transfusion (for fusion surgery P=0.011, OR: 2.627, 95%CI: 1.574-2.782; for scoliosis surgery P<0.001, OR: 2.268, 95%CI: 2.143-2.504) and allogeneic transfusion (for fusion surgeryP<0.001, OR: 6.487, 95%CI: 2.349-17.915; for scoliosis surgery P<0.001, OR: 3.636, 95%CI: 2.389-5.231).Conclusions Intraoperative blood transfusion might be an early-warning indicator for perioperative HBL.