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Strumal carcinoid tumors of the ovary are rare neoplasms composed of an intimate mixture of thyroid and carcinoid tissues. Although various theories regarding their histogenesis have been proposed, evidence confirming the origin of the carcinoid component has been lacking. We report a case of a 40-year-old female with an ovarian strumal carcinoid arising in the background of a mature cystic teratoma. Morphological and immunohistochemical findings support the hypothesis that the carcinoid component originates from the thyroid follicular epithelium, undergoing neuroendocrine differentiation. A single-cell growth pattern was also identified, expanding the known histological spectrum of strumal carcinoids. Our case provides additional immunohistochemical support for the histogenetic origin of strumal carcinoids, offering new insights into their pathogenesis. Recognizing these distinct patterns of staining and unusual morphology is critical for accurate diagnosis and differentiation from metastatic disease.

Endothelin-1 (ET-1) has been implicated in numerous cardiovascular diseases. While the local expression of ET-1 and its receptors ETA and ETB is increased in many disease states, it is unknown whether up-regulation of the endothelin system is adaptive or pathogenic. To delineate the direct role of ET-1 in the diseased heart and blood vessels independently, we generated transgenic mice with conditional and targeted over-expression of ET-1 in cardiomyocytes and arterial smooth muscle cells, respectively, by employing a tissue-specific tetracycline-regulated gene expression system (Tet-OFF). Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This [ET +] line was bred with one harboring cardiac myocyte-restricted expression of tTA [αMHC-tTA] or arterial smooth muscle-restricted expression of tTA [SM22α-tTA]. Binary transgenic mice with cardiac-specific over-expression of human ET-1 [BT: ET+/αMHC-tTA+] demonstrated progressive mortality between 5–11 weeks after DOX withdrawal, associated with an interstitial inflammatory infiltrate, nuclear NF-κB translocation and increased expression of TNF-α, IFN-γ, IL-1 and IL-6. Survival in BT mice was prolonged with the administration of a combined ETA/ET B antagonist but not an ETA-selective antagonist, consistent with a role for ETB in this model. These are the first data to demonstrate that cardiac over-expression of ET-1 is sufficient to induce an inflammatory cascade and dilated cardiomyopathy, leading to heart failure and death. Binary transgenic mice with arterial-specific over-expression of human ET-1 [BT: ET+/SM22α-tTA+] demonstrated an increase in tail systolic blood pressure at 3 week following DOX withdrawal, associated with an impaired acetylcholine-mediated vasorelaxation, increased collagen deposition, and attenuated ET-1-mediated vasoconstriction, as compared to non-BT or DOX-treated BT. However, the mRNA level of ET-1 in aortae of BT mice at 6 week was decreased compared to those at 3 week following DOX withdrawal. Concomitantly, endothelial function, vasoconstrictor responses to ET-1 and blood pressure in BT mice at 6 week following DOX withdrawal no longer differed from non-BT mice. These data showed that 3 weeks of SM22α promoter-defined over-expression of ET-1 is sufficient to cause an increase in blood pressure, but that subsequent reduction of ET-1 over-expression in this model limits the duration of the observed phenotype.

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants’ effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues atwhich variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab ( n  = 321) or placebo ( n  = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P  = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo ( P  < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy. In the phase 2 PASSPORT study, treatment with the anti-tau antibody gosuranemab did not show clinical benefit in participants with supranuclear palsy, suggesting that N-terminal tau neutralization does not translate into clinical efficacy.

In recent years, there has been an increase in the use of accelerated diagnostic protocols (ADPs) and high-sensitivity troponin assays (hsTn) for the assessment of chest pain in emergency departments (EDs). This study aimed to quantitatively summarize the operational and clinical outcomes of ADPs implemented for patients with suspected cardiac chest pain. To be considered eligible for inclusion, studies must have implemented some form of ADP within the ED for evaluating adult (age ≥18 years) patients presenting with chest pain using Tn assays. The primary outcome was ED length of stay (LOS). Secondary outcomes included the proportion of patients admitted and the proportion with 30-day major adverse cardiac events (MACE). Thirty-seven articles involving 404,566 patients met the inclusion criteria, including five randomized controlled trials (RCTs) and 32 observational studies. A significant reduction in total ED LOS was reported in 22 observational studies and four RCTs. Emergency departments with longer baseline ED LOS showed significantly larger reductions in LOS after ADP implementation. This observed association persisted after adjusting for both the change in serial Tn measurement interval and transition from conventional Tn assay to an hsTn assay (β = -0.26; 95% CI, -0.43 to -0.10). Three studies reported an increase in the proportion of patients admitted after introducing an ADP, one of which was significant while 15 studies reported a significant decrease in admission proportion. There was moderate heterogeneity among the 13 studies that reported MACE proportions, with a non-significant pooled risk ratio of 0.95 (95% CI, 0.86−1.04). Implementation of ADPs for chest pain presentations decreases ED LOS, most noticeably within sites with a high baseline LOS; this decreased LOS is seen even in the absence of any change in troponin assay type. The decrease in LOS occurred alongside reductions in hospital admissions, while not increasing MACE. The observed benefits translated across multiple countries and health regions.

It has long been assumed that p53 suppresses tumor development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence 1 , 2 . However, combined deficiency in these three processes does not result in spontaneous tumor formation as observed upon loss of p53, suggesting the existence of additional mechanisms that are critical mediators of p53-dependent tumor suppression function 3 – 5 . To define such mechanisms, we performed in vivo shRNA screens targeting p53-regulated genes in sensitized genetic backgrounds. We found that knockdown of Zmat3, Ctsf and Cav1 , promoted lymphoma/leukemia development only when PUMA and p21, the critical effectors of p53-driven apoptosis, cell cycle arrest and senescence, were also absent. Notably, loss of the DNA repair gene Mlh1 caused lymphoma in a wild-type background, and its enforced expression was able to delay tumor development driven by loss of p53. Further examination of direct p53 target genes implicated in DNA repair showed that knockdown of Mlh1 , Msh2 , Rnf144b , Cav1 and Ddit4 accelerated MYC-driven lymphoma development to a similar extent as knockdown of p53. Collectively, these findings demonstrate that extensive functional overlap of several p53-regulated processes safeguards against cancer and that coordination of DNA repair appears to be an important process by which p53 suppresses tumor development. In vivo shRNA screens in sensitized genetic backgrounds identify p53-activated target genes involved in DNA repair that enable its tumor suppressor function.

Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68 + monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8 + T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68 + monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need. Although immune checkpoint blockade is a standard treatment for patients with malignant mesothelioma, only a minority of patients exhibit radiological response. In a phase II clinical trial (MIST4) investigating the efficacy, safety and molecular correlates of response following treatment with atezolizumab and bevacizumab, the authors demonstrate that the gut microbiota may modulate responsiveness to treatment.

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli . Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals  <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data. In an inter-laboratory study, the authors compare the accuracy and performance of three optical density calibration protocols (colloidal silica, serial dilution of silica microspheres, and colony-forming unit (CFU) assay). They demonstrate that serial dilution of silica microspheres is the best of these tested protocols, allowing precise and robust calibration that is easily assessed for quality control and can also evaluate the effective linear range of an instrument.

Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)–protein kinase A (PKA) signaling pathway by the β 2 adrenergic receptor (encoded by ADRB2 ). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo . These data identify β-adrenergic activation of the cAMP–PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.