A new nomogram prediction model for pulmonary embolism in older hospitalized patients.

Purpose: Diagnosing pulmonary embolism (PE) in older adults is relatively difficult because of the atypical clinical symptoms of PE in older adults accompanied by multiple complications. This study aimed to establish a nomogram model to better predict the occurrence of PE in older adults. Methods: Data were collected from older patients (≥65 years old) with suspected PE who were hospitalized between January 2012 and July 2021 and received confirmatory tests (computed tomographic pulmonary angiography or ventilation/perfusion scanning). The PE group and non-PE (control) group were compared using univariable and multivariable analyses to identify independent risk factors. A nomogram prediction model was constructed with independent risk factors and verified internally. The effectiveness of the nomogram model, Wells score, and revised Geneva score was assessed using the area under the receiver operating characteristic curve (AUC). Results: In total, 447 eligible older patients (290 PE patients and 157 non-PE patients) were enrolled. Logistic regression analysis revealed nine independent risk factors: smoking, inflammation, dyspnea, syncope, mean corpuscular hemoglobin concentration, indirect bilirubin, uric acid, left atrial diameter, and internal diameter of the pulmonary artery. The AUC, sensitivity, and specificity of the nomogram prediction model were 0.763 (95 % confidence interval, 0.721-0.802), 74.48 %, and 67.52 %, respectively. The nomogram showed superior AUC compared to the Wells score (0.763 vs. 0.539, P < 0.0001) and the revised Geneva score (0.763 vs. 0.605, P < 0.0001). Conclusions: This novel nomogram may be a useful tool to better recognize PE in hospitalized older adults.

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.

Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma.

PURPOSE: Chromosome 1 (chr1) copy-number abnormalities (CNA) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and are associated with a heterogeneous impact on outcomes, the drivers of which are largely unknown. EXPERIMENTAL DESIGN: A multiomic approach comprising CRISPR, gene mapping of CNAs and SVs, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilization. RESULTS: We identified two distinct groups of gain(1q): focal gains associated with limited gene-expression changes and a neutral prognosis, and whole-arm gains, which are associated with substantial gene-expression changes, complex genetics, and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT), and two of templated insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants. CONCLUSIONS: Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.

Bronchoscopic instillation of amphotericin B is a safe and effective measure to treat pulmonary mycosis.

Background and objectives: In recent years, there has been a significant increase in the prevalence of pulmonary mycosis disease, and its mortality has increased. There are very few studies on treating pulmonary mycosiss with bronchoscopic instillation of amphotericin B. This study investigated the clinical efficacy and safety of bronchoscopic instillation of amphotericin B for treating pulmonary mycosiss. Methods: This was a multi-centre, retrospective clinical study of 80 patients with pulmonary mycosiss who were treated with bronchoscopic instillation of amphotericin B. The efficacy and safety of this treatment were evaluated. Results: Eighty patients were included {51 males; mean [standard deviation (SD)] age, 46 (15.9) years}. The most common underlying cause was haematological malignancy (73.75%). The mean number of bronchoscopic instillations of amphotericin B was 2.4 (SD 1.5). In terms of treatment success, 58 (72.5%) patients achieved complete or partial changes on imaging after treatment. A total of 62 (77.5%) patients achieved complete or partial changes on imaging and/or local limitation of the mycosis infection. Seventy-six (95%) patients achieved complete or partial changes on imaging and/or local limitation of mycosis infection and/or an immunotherapy time window. The efficacy rates for treatment of Aspergillus and Mucor infections in terms of the three treatment success criteria described above were 73.81% vs. 63.64%, 80.95% vs. 72.73%, and 92.86% vs. 90.91%, respectively. Conclusion: Bronchoscopic instillation of amphotericin B is safe and effective for treatment of pulmonary mycosiss.

Primary empty sella syndrome-caused rhabdomyolysis misdiagnosed as recurrent sepsis: a case report and literature review.

We reported a case of a 68-year-old man who presented with recurrent fever and multiorgan dysfunction. His significantly elevated procalcitonin and C-reactive protein levels indicated recurrent sepsis. However, no focus of infection and no pathogens were identified through a variety of examinations and tests. Although the increase of creatine kinase was less than five times the upper limit of normal value, the diagnosis of rhabdomyolysis secondary to adrenal insufficiency resulting from primary empty sella syndrome was finally made, as supported by serum myoglobin elevation, serum cortisol, and adrenocorticotropic hormone deficiency, bilateral adrenal atrophy on computed tomography, and empty sella on magnetic resonance imaging. After the glucocorticoid replacement treatment, the patient's myoglobin gradually returned to normal range, and his condition continued to improve. Rhabdomyolysis resulting from a rare cause may be misdiagnosed as sepsis in patients who present with increased procalcitonin levels.

Antioxidant capacity, flavor and physicochemical properties of FH06 functional beverage fermented by lactic acid bacteria: a promising method to improve antioxidant activity and flavor of plant functional beverage.

The ability of natural plants to treat chronic diseases is closely related to their antioxidant function. Lactic acid bacteria (LAB) fermentation is an effective way to improve the nutritional value, biological activity and flavor of food. This study investigated the pH, titratable acidity, total polysaccharide, total flavone, total saponin, total polyphenol, and antioxidant activity of the FH06 beverage before and after probiotic fermentation. Results: After fermentation, FH06 had lower contents of total polysaccharides, total flavonoids, total saponins and total polyphenols but higher titratable acidity. The antioxidant activity was tested by total antioxidant capacity (FRAP method) and DPPH· scavenging ability. The FRAP value significantly increased after fermentation (P < 0.05), and the maximum increase was observed for Lactobacillus fermentum grx08 at 25.87%. For DPPH· scavenging ability, the value of all fermentations decreased, and L. fermentum grx08 had the smallest reduction at 2.21% (P < 0.05). The results of GC-MS and sensory analysis showed that fermentation eliminated bad flavors, such as grass, cassia and bitterness, and highlighted the fruit aroma and soft sour taste. Conclusion: The FRAP value and sensory flavor of FH06 fermentation by L. fermentum grx08 were significantly improved, indicating its great potential as a functional food with both strong antioxidant activity and good flavor. Supplementary Information: The online version contains supplementary material available at 10.1186/s13765-022-00762-2.

More than one route to render tumors resistant to cGAS/STING activation.

STING (stimulator of interferon genes) activation has considerable potential as a new strategy for cancer therapy, but clinical results have not been encouraging. Recent studies by Hong et al. and Li et al. explain why STING agonists often fail to regress human tumors and propose combinatorial strategies to overcome the protumor effects of STING activation.

Taxifolin ameliorates lipopolysaccharide-induced intestinal epithelial barrier dysfunction via attenuating NF-kappa B/MLCK pathway in a Caco-2 cell monolayer model.

Intestinal epithelial barrier dysfunction can cause several intestinal diseases. Flavonoids have been shown to be beneficial to the intestinal epithelial barrier function. However, the effects of taxifolin (TAX), a naturally occurring flavonoid, on the intestinal epithelial barrier function are unclear. Thus, the aims of this study were to investigate the protective effect and potential mechanism of TAX against lipopolysaccharide (LPS)-induced intestinal epithelial barrier dysfunction in a Caco-2 cell monolayer model. Our results showed that TAX increased the transepithelial electrical resistance (TEER) and decreased the fluorescein isothiocyanate (FITC)-dextran (4 kDa) flux in the damaged intestinal epithelial barrier. Meanwhile, TAX inhibited an LPS-induced decrease in mRNA and protein expression of tight junction (TJ) proteins (claudin-1, zonula occludens [ZO]-1, and occludin), and ameliorating the continuous distribution pattern disrupted of TJs. These results suggested that TAX ameliorated intestinal epithelial barrier dysfunction. Regarding the underlying mechanism, TAX reduced the LPS-induced secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in Caco-2 cell monolayers. In addition, TAX suppressed the phosphorylation of nuclear factor kappa-B (NF-κB), inhibitor protein of NF-κBα (IκBα), and myosin light chain (MLC), and downregulated the expression of myosin light chain kinase (MLCK) in LPS-treated Caco-2 cells. In summary, TAX can maintain TJ proteins by inhibiting the NF-κB/MLCK pathway and pro-inflammatory factor secretion to ameliorate LPS-induced intestinal epithelial barrier dysfunction. Thus, TAX is a promising candidate agent for use in functional food to ameliorate intestinal barrier dysfunction.

The efficacy and mechanism of thoracic photodynamic therapy mediated by hematoporphyrin injection on disseminated pleural malignancies of Lewis lung carcinoma in mice.

In order to avoid the problems of long exposure time and high incidence of photosensitivity by intravenous injection of photosensitizer, our study explore the safety, efficacy, and possible mechanisms of photodynamic therapy (PDT) by intrathoracic administration of hematoporphyrin injection in the treatment of disseminated pleural malignancies of Lewis lung carcinoma in mice to provide a theoretical basis for thoracic PDT in the clinic. Hematoporphyrin was administered into the thoracic cavity of tumor-bearing mice, and the concentrations of hematoporphyrin in normal and tumor pleural tissues were detected by high-performance liquid chromatography. The tumor-bearing mice were randomly divided into four groups: model control, pure laser irradiation, PDT low-dose, and PDT high-dose groups. Hematoxylin and eosin (H&E) staining was used to observe the histological changes in normal pleural tissue. H&E and DNA in situ nick end-labeling staining were used to detect necrosis and apoptosis in the tumor tissues. The tumor volume in each group from high to low was as follows: model control group > pure laser irradiation group > PDT low-dose group > PDT high-dose group. Inflammatory cells infiltrated the normal pleural tissue of the PDT group. Necrosis was observed to different extents in the tumor tissues of the PDT group. The apoptosis index of each group from high to low was as follows: PDT high-dose group > PDT low-dose group > pure laser irradiation group > model control group. The differences were statistically significant (P<0.05). Hematoporphyrin selectively accumulated in tumor pleural tissues. PDT with intrathoracic administration of hematoporphyrin injection could inhibit the thoracic implant tumors in mice by inducing necrosis and apoptosis.

Blocking PI3K p110ß Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer.

A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110ß dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110ß inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110ß/RAC/PAK1 and ß-catenin pathways in CRPC, we found that combining p110ß with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110ß activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC. IMPLICATIONS: This work establishes p110ß as a promising target for preventing the progression of primary PTEN-deficient prostate tumors to CRPC, and for treating established CRPC in combination with RAC/PAK1 or tankyrase inhibitors.

Chromothripsis as a pathogenic driver of multiple myeloma.

Analysis of the genetic basis for multiple myeloma (MM) has informed many of our current concepts of the biology that underlies disease initiation and progression. Studying these events in further detail is predicted to deliver important insights into its pathogenesis, prognosis and treatment. Information from whole genome sequencing of structural variation is revealing the role of these events as drivers of MM. In particular, we discuss how the insights we have gained from studying chromothripsis suggest that it can be used to provide information on disease initiation and that, as a consequence, it can be used for the clinical classification of myeloma precursor diseases allowing for early intervention and prognostic determination. For newly diagnosed MM, the integration of information on the presence of chromothripsis has the potential to significantly enhance current risk prediction strategies and to better characterize patients with high-risk disease biology. In this article we summarize the genetic basis for MM and the role played by chromothripsis as a critical pathogenic factor active at early disease phases.

Plasma cells expression from smouldering myeloma to myeloma reveals the importance of the PRC2 complex, cell cycle progression, and the divergent evolutionary pathways within the different molecular subgroups.

Sequencing studies have shed some light on the pathogenesis of progression from smouldering multiple myeloma (SMM) and symptomatic multiple myeloma (MM). Given the scarcity of smouldering samples, little data are available to determine which translational programmes are dysregulated and whether the mechanisms of progression are uniform across the main molecular subgroups. In this work, we investigated 223 SMM and 1348 MM samples from the University of Arkansas for Medical Sciences (UAMS) for which we had gene expression profiling (GEP). Patients were analysed by TC-7 subgroup for gene expression changes between SMM and MM. Among the commonly dysregulated genes in each subgroup, PHF19 and EZH2 highlight the importance of the PRC2.1 complex. We show that subgroup specific differences exist even at the SMM stage of disease with different biological features driving progression within each TC molecular subgroup. These data suggest that MMSET SMM has already transformed, but that the other precursor diseases are distinct clinical entities from their symptomatic counterpart.

Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer.

Despite  improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.

Metagenomic Next-Generation Sequencing for Pulmonary Fungal Infection Diagnosis: Lung Biopsy versus Bronchoalveolar Lavage Fluid.

PURPOSE: Metagenomic next-generation sequencing (mNGS) is widely used for pulmonary infection; nonetheless, the experience from its clinical use in diagnosing pulmonary fungal infections is sparse. This study aimed to compare mNGS results from lung biopsy and bronchoalveolar lavage fluid (BALF) and determine their clinical diagnostic efficacy. PATIENTS AND METHODS: A total of 106 patients with suspected pulmonary fungal infection from May 2018 to January 2020 were included in this retrospective study. All patients' lung biopsy and BALF specimens were collected through bronchoscopy. Overall, 45 (42.5%) patients had pulmonary fungal infection. The performance of lung biopsy and BALF used for mNGS in diagnosing pulmonary fungal infections and identifying pathogens was compared. Additionally, mNGS was compared with conventional tests (pathology, galactomannan test, and cultures) with respect to the diagnosis of pulmonary fungal infections. RESULTS: Lung biopsy-mNGS and BALF-mNGS exhibited no difference in terms of sensitivity (80.0% vs 84.4%, P=0.754) and specificity (91.8% vs 85.3%, P=0.39). Additionally, there was no difference in specificity between mNGS and conventional tests; however, the sensitivity of mNGS (lung biopsy, BALF) in diagnosing pulmonary fungal infections was significantly higher than that of conventional tests (conventional tests vs biopsy-mNGS: 44.4% vs 80.0%, P<0.05; conventional tests vs BALF-mNGS: 44.4% vs 84.4%, P<0.05). Among 32 patients with positive mNGS results for both biopsy and BALF specimens, 23 (71.9%) cases of consistency between the two tests for the detected fungi and nine (28.1%) cases of a partial match were identified. Receiver operating curve analysis revealed that the area under the curve for the combination of biopsy and BALF was significantly higher than that for BALF-mNGS (P=0.018). CONCLUSION: We recommend biopsy-based or BALF-based mNGS for diagnosing pulmonary fungal infections because of their diagnostic advantages over conventional tests. The combination of biopsy and BALF for mNGS can be considered when higher diagnostic efficacy is required.

Expression of claudin-8 is induced by aldosterone in renal collecting duct principal cells.

Fine tuning of Na+ reabsorption takes place along the aldosterone-sensitive distal nephron, which includes the collecting duct (CD), where it is mainly regulated by aldosterone. In the CD, Na+ reabsorption is mediated by the epithelial Na+ channel and Na+ pump (Na+-K+-ATPase). Paracellular ion permeability is mainly dependent on tight junction permeability. Claudin-8 is one of the main tight junction proteins expressed along the aldosterone-sensitive distal nephron. We have previously shown a coupling between transcellular Na+ reabsorption and paracellular Na+ barrier. We hypothesized that aldosterone controls the expression levels of both transcellular Na+ transporters and paracellular claudin-8 in a coordinated manner. Here, we show that aldosterone increased mRNA and protein levels as well as lateral membrane localization of claudin-8 in cultured CD principal cells. The increase in claudin-8 mRNA levels in response to aldosterone was prevented by preincubation with 17-hydroxyprogesterone, a mineralocorticoid receptor antagonist, and by inhibition of transcription with actinomycin D. We also showed that a low-salt diet, which stimulated aldosterone secretion, was associated with increased claudin-8 abundance in the mouse kidney. Reciprocally, mice subjected to a high-salt diet, which inhibits aldosterone secretion, or treated with spironolactone, a mineralocorticoid receptor antagonist, displayed decreased claudin-8 expression. Inhibition of glycogen synthase kinase-3, Lyn, and Abl signaling pathways prevented the effect of aldosterone on claudin-8 mRNA and protein abundance, suggesting that signaling of protein kinases plays a permissive role on the transcriptional activity of the mineralocorticoid receptor. This study shows that signaling via multiple protein kinases working in concert mediates aldosterone-induced claudin-8 expression in the CD.NEW & NOTEWORTHY In this study, we showed that aldosterone modulates claudin-8 expression in cultured collecting duct principal cells and in the mouse kidney. The upregulation of claudin-8 expression in response to aldosterone is dependent on at least glycogen synthase kinase-3, Lyn, and Abl signaling pathways, indicating the participation of multiple protein kinases to the effect of aldosterone.

Early-Released Interleukin-10 Significantly Inhibits Lipopolysaccharide-Elicited Neuroinflammation In Vitro.

Anti-inflammatory cytokine interleukin (IL)-10 is pivotal for limiting excessive inflammation in the central nervous system. Reports show that lipopolysaccharide (LPS)-induced microglial IL-10 emerges in a delayed manner in vitro and in vivo, lagging behind proinflammatory cytokines to facilitate the resolution of neuroinflammation. We hypothesized that IL-10 releases quite quickly based on our pilot investigation. Here, we uncovered a bimodal expression of microglial IL-10 gene transcription induced by LPS in mouse primary mixed glial cultures. This pattern consisted of a short brief early-phase and a long-lived late-phase, enabling the production of IL-10 protein in a rapid manner. The removal and addition of IL-10 protein assays indicated that early-released IL-10 exerted potent modulatory effects on neuroinflammation at picomolar levels, and IL-10 released at the onset of neuroinflammation is tightly controlled. We further showed that the early-released, but not the late-released, IL-10 was crucial for mediating and potentiating the anti-inflammatory function of a ß2-adrenergic receptor agonist salmeterol. This study in vitro highlights the essential role of early-released IL-10 in regulating the appropriate degree of neuroinflammation, overturning the previous notion that microglial IL-10 produces and functions in a delayed manner and providing new insights into anti-inflammatory mechanisms-mediated neuroimmune homeostasis.

The Mediator captures CDK7, an attractive transcriptional target in cancer.

Cyclin-dependent kinase 7 (CDK7) is implicated in regulating the expression of cancer-dependent genes, and multiple CDK7-targeted therapies are currently under clinical investigation. Three recent studies elucidate the structure of human transcription machinery, offering vital mechanistic insights into CDK7 function and a potential pharmacodynamic marker of CDK7 activity in tumors.

SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling.

KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.