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Background We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. Methods Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. Results Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P Conclusions Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

Context: COVID-19 related to SARS-CoV-2 infection generates inflammation with increased reactive oxygen species production. Drug treatment and others factors could influence systemic oxidative stress during pathogenic insult. Aims: To determine the redox status in COVID-19 patients with different clinical conditions and explore the relationship between redox and hematological hemochemical variables. Methods: In this comparative longitudinal study, blood samples were drawn from 160 individuals divided into four groups: COVID-19 asymptomatic, COVID-19 symptomatic (low and moderate symptoms), COVID-19 convalescent, and presumable healthy subjects. Demographic, redox, hematological, and hemochemical indices were assessed. Statistical analyses compared the median values of each variable and explored individual, simultaneous indices, and multivariate alteration. Results: Relative to the healthy group, acute COVID-19, and convalescent groups had significant differences in global damage indices and antioxidant status (p

To evaluate postoperative and oncologic outcomes associated with pelvic exenteration for non-ovarian gynecologic malignancies.This was a retrospective review of patients who underwent pelvic exenteration for non-ovarian gynecologic malignancies at our institution from 1/1/2010-12/31/2019. Palliative exenteration cases were excluded from survival analysis. Postoperative complications were early (≤30 days) or late (31-180 days). Complications were graded using a validated institutional scale. Major complications were considered grade ≥ 3. Categorical variables were compared using the chi-square test, and the Kaplan-Meier method was used for survival analysis.Of 100 patients identified, 89 underwent pelvic exenteration for recurrent disease, 5 for palliation, 5 for primary disease, and 1 for persistent disease. Thirty percent had cervical, 27% vulvar, 24% uterine, and 19% vaginal cancer. Sixty-two percent underwent total, 30% anterior, and 8% posterior exenteration. No deaths occurred intraoperatively or within 30 days of surgery. Six patients died after 30 days. Ninety-seven experienced a perioperative complication-49 early, 1 late, and 47 both. Fifty experienced a major complication-22 (44%) early, 19 (38%) late, and 9 (18%) both. No variables were statistically associated with complication development. The 3-year progression-free survival rate was 61.0%; the 3-year overall survival rate was 61.6%. Of 58 surviving patients, 16 (28%) and 4 (7%) were alive after 5 and 10 years, respectively.The overall complication rate for pelvic exenteration remains high. No variables demonstrated association with complication development as the rate was nearly 100%. The low rate of perioperative mortality is likely due to improved perioperative care.

Soil-transmitted helminths cause widespread disease, infecting ~1.5 billion people living within poverty-stricken regions of tropical and subtropical countries. As adult worms inhabit the intestine alongside bacterial communities, we determined whether the bacterial microbiota impacted on host resistance against intestinal helminth infection. We infected germ-free, antibiotic-treated and specific pathogen-free mice, with the intestinal helminth Heligmosomoides polygyrus bakeri. Mice harboured increased parasite numbers in the absence of a bacterial microbiota, despite mounting a robust helminth-induced type 2 immune response. Alterations to parasite behaviour could already be observed at early time points following infection, including more proximal distribution of infective larvae along the intestinal tract and increased migration in a Baermann assay. Mice lacking a complex bacterial microbiota exhibited reduced levels of intestinal acetylcholine, a major excitatory intestinal neurotransmitter that promotes intestinal transit by activating muscarinic receptors. Both intestinal motility and host resistance against larval infection were restored by treatment with the muscarinic agonist bethanechol. These data provide evidence that a complex bacterial microbiota provides the host with resistance against intestinal helminths via its ability to regulate intestinal motility.

Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown. Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material. Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment.

Purpose: To increase the understanding of the IoT by demonstrating its impacts and benefits on supply chain performance. Design/methodology/approach: System dynamic simulation modeling to estimate IoT impacts on supply chain performance, based on a previously proposed framework and its propositions. Findings: In general, simulation results show a positive impact on the supply chain activities where the propositions targeted. Specifically: P2: better decision-making. – The study case shows better asset utilization, and reduced shipping time. However, transportation costs increase because of the lack of a decision-making system. P3: enhanced supply chain connectivity/collaboration/integration. – The study case shows that benefits of supply chain integration through demand planning can be obtained. P5: reduced lead-time. – The study Case shows a reduced shipping time when location technology and when all technologies are combined. P6: better asset utilization. – The study Case shows a higher utilization factor, hinting a better asset utilization even without a decision-making system. Research limitations/implications: The models here presented are based on merged data from different sources: Primary and secondary sources, and estimates based on assumptions. The mere nature of the base-data limits the precision of results. Practical implications: The implementation of data collection or data transmission technologies alone is not sufficient to obtain full benefits. A decision-making processing system, that integrates the complete array of appropriated technologies, should also be implemented. This the underlying concept and the contribution of the IoT.

To assess long-term outcomes with robotic versus laparoscopic/thoracoscopic and open surgery for colorectal, urologic, endometrial, cervical, and thoracic cancers.Minimally invasive surgery provides perioperative benefits and similar oncological outcomes compared with open surgery. Recent robotic surgery data have questioned long-term benefits.A systematic review and meta-analysis of cancer outcomes based on surgical approach was conducted based on PRISMA guidelines using Pubmed, Scopus, and Embase. HRs for recurrence, disease-free survival (DFS), and overall survival (OS) were extracted/estimated using a hierarchical decision-tree and pooled in RevMan 5.4 using inverse-variance fixed effect (heterogeneity non-significant) or random effect models.Of 31,204 references, 199 were included (7 randomized, 23 database, 15 prospective, 154 retrospective studies)-157,876 robotic, 68,007 laparoscopic/thoracoscopic, and 234,649 open cases. Cervical cancer: OS and DFS were similar between robotic and laparoscopic (1.01[0.56, 1.80], P=0.98) or open (1.18[0.99, 1.41], P=0.06) surgery; two papers reported less recurrence with open surgery (2.30[1.32, 4.01], P=0.003). Endometrial cancer: the only significant result favored robotic over open surgery (OS; 0.77[0.71, 0.83], P0.001). Lobectomy: DFS favored robotic over thoracoscopic surgery (0.74[0.59, 0.93], P=0.009); OS favored robotic over open surgery (0.93[0.87, 1.00], P=0.04). Prostatectomy: recurrence was less with robotic versus laparoscopic surgery (0.77[0.68, 0.87], P0.0001); OS favored robotic over open surgery (0.78[0.72, 0.85], P0.0001). Low-anterior resection: OS significantly favored robotic over laparoscopic (0.76[0.63, 0.91], P=0.004) and open surgery (0.83[0.74, 0.93], P=0.001).Long-term outcomes were similar for robotic versus laparoscopic/thoracoscopic and open surgery, with no safety signal or indication requiring further research (PROSPERO Reg#CRD42021240519).

La internacionalización de la educación ayuda a aprovechar las oportunidades laborales y de mejora en la calidad de vida que ofrece la creciente interdependencia económica mundial y, aunque por lo regular se ha practicado en universidades e instituciones de educación superior, recientemente algunos gobiernos nacionales la han incorporado a sus políticas de desarrollo regional. Quizás por ser recientes, las políticas públicas de internacionalización de la educación superior no han sido ampliamente estudiadas; no obstante, los estudios realizados muestran que su operación y resultados están influidos por la forma en que se implantan y por la efectividad de los actores que participan en la implantación. En este trabajo, se reportan los resultados de un estudio sobre la implantación del Programa Proyecta 100,000 de intercambio binacional de estudiantes de educación superior entre México y Estados Unidos, establecido en 2013 con el patrocinio de los gobiernos de ambos países, y cuya última promoción se dio en 2018. Con la ayuda del análisis de regresión, aplicado a información proveniente de una encuesta realizada entre sus becarios por los responsables en 2015, el Programa es evaluado a través del contraste de la hipótesis de trabajo que afirma que la participación de numerosos actores de diferentes instancias gubernativas, dificultan la implantación exitosa del Programa. Los resultados muestran que sus becarios califican bastante bien la operación del Programa, así como el impacto y la satisfacción que derivaron de su participación en él. Manifiestan también haber encontrado dificultades con los procesos del Programa, aunque ellas no son directamente asociadas con sus responsables, que en efecto son múltiples y provienen de diferentes instancias gubernativas, sino que tienen que ver más con su orientación hacia sólo el aprendizaje del idioma, en estancias demasiado cortas en el exterior y con becas insuficientes. Por ello, se considera que, al ser subsanadas esas dificultades, se podría lograr un mayor impacto positivo entre la población objetivo del Programa, que podría ser reanudado sin reservas de ese tipo.

ObjectiveTo assess potential predictive variables for nodal metastasis and survival outcomes in patients with newly diagnosed, low-grade endometrial stromal sarcoma.MethodsWe performed a single-institution, retrospective analysis of consecutive patients with newly diagnosed, low-grade endometrial stromal sarcoma who presented between January 1, 1980 and December 31, 2019 and underwent hysterectomy at our institution or presented within 3 months of primary surgery elsewhere before recurrence. Patients who presented to our institution only at recurrence were excluded. Patients with ResultsWe identified 127 consecutive patients for analysis. Median age at diagnosis was 48 years (range 19–88 years); 91 (74.6%) of 127 were pre-menopausal; and 74 (58.3%) of 127 had uterine-confined, stage I tumors. Of 56 patients (44.1%) who underwent lymph node sampling, 10 (17.9%) had nodal metastasis. Of the 10 with nodal metastasis, 1 (10%) did not have lymphadenopathy or extra-uterine disease, 4 (40%) had lymphadenopathy only, 1 (10%) had extra-uterine disease only, and 4 (40%) had both. Among the 29 patients without apparent extra-uterine disease or gross lymphadenopathy, there was one occult lymph node metastasis (3.4%). Gross lymphadenopathy at time of surgery was predictive for lymph node metastasis (pConclusionsLymph node dissection in patients with low-grade endometrial stromal sarcoma should be reserved for those with clinically suspicious lymphadenopathy. Disease stage correlated with progression-free survival but not disease-specific survival. Post-operative therapy did not improve progression-free survival or disease-specific survival.

OBJECTIVE: To assess survival among patients diagnosed with uterine carcinosarcoma (CS) who underwent sentinel lymph node (SLN) biopsy alone vs. systematic lymph node dissection (LND). METHODS: We identified newly diagnosed CS patients who underwent primary surgical management from January 1996–December 2019. The SLN cohort underwent SLN biopsy alone with bilateral SLNs identified. The systematic LND cohort did not undergo SLN biopsy. RESULTS: Ninety-nine patients underwent SLN biopsy, and 100 patients underwent systematic LND. There was no difference by age, stage, body mass index, myoinvasion (

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To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45− cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0–18) and, at 36 days posttreatment, was 4 (range, 0–17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79–0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32–1.03) and PFS (HR, 0.59; 95% CI, 0.36–0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

Càncer de coll uterí; Platí; Topotecan Cáncer de cuello uterino; Platino; Topotecan Cervical cancer; Platinum; Topotecan Objective To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma. Methods Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2 days 1–3 (n = 223) vs cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS. Results At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91–1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82–1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86–1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86–1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75–1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones. Conclusions Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. This study was supported by the following National Cancer Institute and Genentech grants: NRG Oncology (1U10CA180822), NRG Operations (U10CA180868) and NCORP grant UG1CA189867.

Exposure of human monocytes to lipopolysaccharide (LPS) or other pathogen-associated molecular pattern (PAMPs) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance (ET), associated with the pathogenesis of sepsis. In this study, we aimed to characterize the cellular state of human monocytes from healthy donors stimulated with Staphylococcus aureus in comparison to TLR2-specific ligands. We analyzed S. aureus induced gene expression changes after 2 and 24 hours by amplicon sequencing (RNA-AmpliSeq) and compared the pro-inflammatory response after 2 hours with the response in re-stimulation experiments. In parallel, glycoprotein expression changes in human monocytes after 24 hours of S. aureus stimulation were analyzed by proteomics and compared to stimulation experiments with TLR2 ligands Malp-2 and Pam3Cys and TLR4 ligand LPS. Finally, we analyzed peripheral blood monocytes of patients with S. aureus bloodstream infection for their ex vivo inflammatory responses towards S. aureus stimulation and their glycoprotein expression profiles. Our results demonstrate that monocytes from healthy donors stimulated with S. aureus and TLR ligands of Gram-positive bacteria entered the tolerant cell state after activation similar to LPS treatment. In particular reduced gene expression of pro-inflammatory cytokines (TNF, IL1β) and chemokines (CCL20, CCL3, CCL4, CXCL2, CXCL3 and CXCL8) could be demonstrated. Glycoprotein expression changes in monocytes tolerized by the different TLR agonists were highly similar while S. aureus-stimulated monocytes shared some of the PAMP-induced changes but also exhibited a distinct expression profile. 11 glycoproteins (CD44, CD274, DSC2, ICAM1, LAMP3, LILRB1, PTGS2, SLC1A3, CR1, FGL2, and HP) were similarly up- or downregulated in all four comparisons in the tolerant cell state. Monocytes from patients with S. aureus bacteremia revealed preserved pro-inflammatory responsiveness to S. aureus stimulation ex vivo, expressed increased CD44 mRNA but no other glycoprotein of the tolerance signature was differentially expressed.

The Figure Legend for the Supplemental Figure 1 describes the content of the 3 panels that make up this Supplemental Figure.

This Supplementary Figure contains the GOG 240 trial schema along with the survival curves from the interim analysis and second analysis.

Purpose: In the randomized phase III trial, Gynecologic Oncology Group (GOG) protocol 240, the incorporation of bevacizumab with chemotherapy significantly increased overall survival (OS) in women with advanced cervical cancer. A major objective of GOG-240 was to prospectively analyze previously identified pooled clinical prognostic factors known as the Moore criteria.Experimental Design: Potential negative factors included black race, performance status 1, pelvic disease, prior cisplatin, and progression-free interval Results: For the entire population (n = 452), high-risk patients had significantly worse OS (P < 0.0001). The HRs of death for treating with topotecan in low-risk, mid-risk, and high-risk subsets are 1.18 [95% confidence interval (CI), 0.63–2.24], 1.11 (95% CI, 0.82–1.5), and 0.84 (95% CI, 0.50–1.42), respectively. The HRs of death for treating with bevacizumab in low-risk, mid-risk, and high-risk subsets are 0.96 (95% CI, 0.51–1.83; P = 0.9087), 0.673 (95% CI, 0.5–0.91; P = 0.0094), and 0.536 (95% CI, 0.32–0.905; P = 0.0196), respectively.Conclusions: This is the first prospectively validated scoring system in cervical cancer. The Moore criteria have real-world clinical applicability. Toxicity concerns may justify omission of bevacizumab in some low-risk patients where survival benefit is small. The benefit to receiving bevacizumab appears to be greatest in the moderate- and high-risk subgroups (5.8-month increase in median OS). Clin Cancer Res; 21(24); 5480–7. ©2015 AACR.

Background A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. Methods Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). Results The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes. Conclusions DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

Liver cancer is a malignancy developed from underlying liver disease that encompasses liver injury and metabolic disorders. The progression from these underlying liver disease to cancer is accompanied by chronic inflammatory conditions in which liver macrophages play important roles in orchestrating the inflammatory response. During this process, bioactive lipids produced by hepatocytes and macrophages mediate the inflammatory responses by acting as pro-inflammatory factors, as well as, playing roles in the resolution of inflammation conditions. Here, we review the literature discussing the roles of bioactive lipids in acute and chronic hepatic inflammation and progression to cancer.

Streptococcus pneumoniae-induced hemolytic uremic syndrome (Sp-HUS) is a kidney disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. This disease is frequently underdiagnosed and its pathophysiology is poorly understood. In this work, we compared clinical strains, isolated from infant Sp-HUS patients, to a reference pathogenic strain D39, for host cytotoxicity and further explored the role of Sp-derived extracellular vesicles (EVs) in the pathogenesis of a HUS infection. In comparison with the WT strain, pneumococcal HUS strains caused significant lysis of human erythrocytes and increased the release of hydrogen peroxide. Isolated Sp-HUS EVs were characterized by performing dynamic light-scattering microscopy and proteomic analysis. Sp-HUS strain released EVs at a constant concentration during growth, yet the size of the EVs varied and several subpopulations emerged at later time points. The cargo of the Sp-HUS EVs included several virulence factors at high abundance, i.e., the ribosomal subunit assembly factor BipA, the Pneumococcal Surface Protein A (PspA), the lytic enzyme LytC, several sugar utilization and fatty acid synthesis proteins. Sp-HUS EVs strongly downregulated the expression of the endothelial surface marker PECAM-1 and were internalized by human endothelial cells. Sp-HUS EVs elicited the release of pro-inflammatory cytokines (IL-1ß, IL-6) and chemokines (CCL2, CCL3, CXCL1) by human monocytes. These findings shed new light on the overall function of Sp-EVs, in the scope of infection-mediated HUS, and suggest new avenues of research for exploring the usefulness of Sp-EVs as therapeutic and diagnostic targets.ImportanceStreptococcus pneumoniaeis a life-threatening human pathogen associated with severe illnesses in the upper respiratory tract. Disseminated infections also occur, as the kidney disease hemolytic uremic syndrome. Even though vaccination is available, this pathogen is responsible for a worldwide high mortality rate, especially among children from least developed countries, where vaccination strategies are poor or inexistent. It is estimated that 30% of invasive pneumococcal diseases are caused by antibiotic resistant bacteria, leading to the classification of “serious threat” by the World Health Organization. In order to prevent cases of severe illness, investigation in the direction of new vaccine candidates is of upmost importance. Pneumococcal extracellular vesicles pose as ideal candidates for a serotype-independent vaccine formulation. To this purpose, the aspects of vesicle formation, cargo allocation and function need to be understood in detail.Graphical Abstract

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma.

High circulating lipids occurring in obese individuals and insulin-resistant patients are considered a contributing factor to type 2 diabetes. Exposure to high lipid concentration is proposed to both protect and damage beta-cells under different circumstances. Here, by feeding mice a high-fat diet (HFD) for 2 weeks to up to 14 months, the study showed that HFD initially causes the beta-cells to expand in population, whereas long-term exposure to HFD is associated with failure of beta-cells and the inability of animals to respond to glucose challenge. To prevent the failure of beta-cells and the development of type 2 diabetes, the molecular mechanisms that underlie this biphasic response of beta-cells to lipid exposure were explored. Using palmitic acid (PA) in cultured beta-cells and islets, the study demonstrated that chronic exposure to lipids leads to reduced viability and inhibition of cell cycle progression concurrent with down-regulation of a pro-growth/survival kinase AKT, independent of glucose. This AKT down-regulation by PA is correlated with the induction of mTOR/S6K activity. Inhibiting mTOR activity with rapamycin induced Raptor and restored AKT activity, allowing beta-cells to gain proliferation capacity that was lost after HFD exposure. In summary, a novel mechanism in which lipid exposure may cause the dipole effects on beta-cell growth was elucidated, where mTOR acts as a lipid sensor. These mechanisms can be novel targets for future therapeutic developments.

SummaryMedulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically very heterogenous. To unravel phenotypically relevant MB subtypes, we compiled a harmonized proteome dataset of 167 MBs and integrated findings with DNA methylation and N-glycome data. Six proteome MB subtypes emerged, that could be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pGroup3-Myc), and synapses/immunological processes (pSHHs, pGroup3 and pGroup4). Multiomic analysis revealed different conservation levels of proteome features across MB subtypes at the DNA-methylation level. Aggressive pGroup3-Myc MBs and favorable pWNT MBs were most similar in cluster hierarchies concerning overall proteome patterns but showed different protein abundances of the vincristine resistance associated multiprotein complex TriC/CCT and of N-glycan turnover associated factors. The N-glycome reflected proteome subtypes and complex-bisecting N-glycans characterized pGroup3-Myc tumors. Our results shed light on new targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures.SignificanceWhereas the application of omics technologies has significantly improved MB tumor classification and treatment stratification, it is still of debate, which features predict best clinical outcome. Moreover, treatment options - especially for high-risk groups - are still unsatisfactory. In contrast to nucleic acids, the proteome and their N-glycans may reflect the phenotype of a tumor in a more direct way and thus hold the potential to discover clinically relevant phenotypes and potentially targetable pathways. We show that these analyses are feasible on formalin fixed and paraffine embedded tissue. Compiling a comprehensive MB dataset, we detected new biomarkers and characteristics for high- and low-risk MB subtypes that were not reflected by other omic data modalities before. Specifically, we identified subtype specific abundance differences in proteins of the vincristine resistance associated multiprotein complex TriC/CCT and in proteins involved in N-glycan turnover. Changes in the N-glycans are considered as potential hallmarks of cancer and we show that N-glycan profiles can distinguish MB subtypes. These tumor-specific N-glycan structures hold a strong potential as new biomarkers, as well as immunotherapy targets.Highlights- Integration of in-house proteome data on formalin fixated paraffine embedded medulloblastoma (MB) and publicly available datasets enables large scale proteome analysis of MB- Six proteome MB subtypes can be assigned to two main molecular programs: replication/ translation versus synapse/immune system- Identification and validation of IHC compatible protein-biomarkers for high and low risk MB subtypes, such as TNC and PALMD.- Subtype specific correlation of the DNA methylome and the proteome reveals different conserved molecular characteristics across MB subtypes.- pGroup3-Myc subtype MBs are associated with high-risk features including high abundances of vincristine resistance associated TriC/CCT member proteins- Proteome MB subtypes show differential N-glycosylation patterns, revealing complex-bisecting glycans as potentially immunotargetable hallmarks of the high risk pGroup3-Myc subtype.

Purpose: This study aims to analyze if, during periods of economic recession, the cash position impacts the performance of Brazilian companies. In addition, it seeks to identify if there are differences in the intensity of such relationships for the different sectors in which companies operate. Originality/value: The appropriate management of a company’s cash position is key for the maintenance of its financial health in the long term. This subject is particularly relevant for emerging countries, such as Brazil, considering the track record of frequent economic recessions. Such economic recessions lead to the deterioration of the companies’ operating results and shortage of credit facilities, negatively affecting the companies’ liquidity. In the last decade, studies have been discussing the relevance of the companies’ cash position to improve their performance in periods of financial constraint. Design/methodology/approach: To develop this study, a sample composed of 200 Brazilian companies listed on B3 was used, grouping information from the period between 2013 and 2016, organized in a balanced dynamic panel. Findings: The results obtained through regressions indicate that there is a positive and statistically significant relationship between cash position and the performance of the companies, measured by the return on assets (ROA) – but not by the market to book ratio –, and it was also identified that the sector in which the company operates has a moderating factor on the intensity of such a relationship.

Resumo Objetivo: O presente trabalho analisa se, em momentos de recessão econômica, a posição de caixa tem impacto na performance das empresas brasileiras. Além disso, busca-se identificar se há diferenças na intensidade dessa relação para os diferentes setores de atuação das empresas. Originalidade/valor: A adequada gestão da liquidez das empresas é fundamental para a manutenção da sua saúde financeira e para a sua sustentabilidade econômica em longo prazo. Esse tema é especialmente importante em países emergentes, como o Brasil, que tem um histórico de frequentes recessões econômicas. As recessões levam à piora dos resultados operacionais das empresas e à escassez de linhas de crédito e, portanto, afetam negativamente a liquidez das companhias. Na última década, tem sido discutida a importância do uso de caixa pelas empresas para melhorar sua performance em períodos de restrição financeira. Design/metodologia/abordagem: Para desenvolver este estudo, foi utilizada uma amostra de 200 empresas listadas na B3, agrupando informações do período de 2013 a 2016, organizadas em um painel dinâmico balanceado. Resultados: Os resultados obtidos por meio das regressões indicam que há relação positiva e estatisticamente significante entre a posição de caixa e a performance medida pelo ROA (mas não pelo market to book). Identificou-se também que o setor de atuação da empresa modera a intensidade dessa relação.

Introduction The cIMPACT-NOW update 6 first introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear. Methods We searched the institutional database for patients with: (1) glioblastoma defined by histopathology; and (2) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region. Results We identified 224 patients with glioblastoma diagnosed based on histopathology, and 54 patients with IDHwt astrocytoma with pTERTmut (19 astrocytomas WHO grade II and 38 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two cohorts as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two cohorts when treated with radio- or chemotherapy. In both cohorts, higher numbers of methylated CpG sites were associated with favourable outcome. Conclusions Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both tumor entities, higher numbers of methylated CpG sites appear associated with more favourable outcome. Evaluation in larger prospective cohorts is warranted.

We report a case of a 47-year-old woman with a history of acral lentiginous melanoma, left great toe subungual primary, metastatic to the lungs, brain, and spleen, presenting with lower urinary tract symptoms. She had also palpated and removed a dark mass from her vaginal canal. Magnetic resonance imaging (MRI) showed polypoidal lesions within the urinary bladder and the endometrium. The suspected differential diagnosis was endometrial and bladder melanoma metastases, based on her cancer history and MRI findings. The patient underwent cystoscopy with transurethral resection of the bladder tumor and endometrial biopsy, and pathology was consistent with metastatic melanoma. Bladder and endometrial metastatic lesions are exceedingly rare. Herein, we describe an unusual case of metastatic melanoma concurrent to the urinary bladder and endometrium.

When effective vaccines are available, vaccination programs are typically one of the best defences against the spread of an infectious disease. Unfortunately, vaccination rates may be suboptimal for a prolonged duration as a result of slow uptake of vaccines by the public. Key factors driving slow vaccination uptake can be a complex interaction of vaccine roll-out policies and logistics, and vaccine hesitancy behaviours potentially caused by an inflated sense of risk in adverse reactions in some populations or community complacency in communities that have not yet experienced a large outbreak. In the recent COVID-19 pandemic, public health responses around the world began to include vaccination programs from late 2020 to early 2021 with an aim of relaxing non-pharmaceutical interventions such as lockdowns and travel restrictions. For many jurisdictions there have been challenges in getting vaccination rates high enough to enable the relaxation of restrictions based on non-pharmaceutical interventions. A key concern during this time was vaccine hestitancy behaviours potentially caused by vaccine safety concerns fuelled by misinformation and community complacency in jurisdictions that had seen very low COVID-19 case numbers throughout 2020, such as Australia and New Zealand. We develop a novel stochastic epidemiological model of COVID-19 transmission that incorporates changes in population behaviour relating to responses based on non-pharmaceutical interventions and community vaccine uptake as functions of the reported COVID-19 cases, deaths, and vaccination rates. Through a simulation study, we develop a Bayesian analysis approach to demonstrate that different factors inhibiting the uptake of vaccines by the population can be isolated despite key model parameters being subject to substantial uncertainty. In particular, we are able to identify the presence of vaccine hesitancy in a population using reported case, death and vaccination count data alone. Furthermore, our approach provides insight as to whether the dominant concerns driving hesitancy are related to vaccine safety or complacency. While our simulation study is inspired by the COVID-19 pandemic, our tools and techniques are general and could be enable vaccination programs of various infectious diseases to be adapted rapidly in response to community behaviours moving forward into the future.

The 2005 May 13 eruption was an Earth-directed coronal mass ejection (CME) observed using the Multi-Element Radio-Linked Interferometer Network telescope system in the UK as it traversed the Interplanetary Medium on 2005 May 14. Observations of interplanetary scintillation (IPS) provide information on the solar wind conditions, which include velocities and density. In addition, it is also possible to calculate other parameters related to the turbulence and geometry of density irregularities in the solar wind from observations of IPS. Previous analyses have shown that IPS information can be difficult to interpret when a complex structure is crossing the line of sight since the physical properties of the plasma may change quite drastically with distance from the Sun. In order to compare and relate the internal structure of a CME and its physical changes, with the results from observations of IPS obtained previously, we carried out a numerical simulation of the 2005 May 13 eruptive event as it propagates into the IPM, adapting the geometrical properties derived by IPS analysis. In this work, we give a possible explanation of some signatures of CME sub-structure from the point of view of the IPS technique combined with what the modelling reveals.

This paper presents a system of cyclic tensor algebra for operations involving fourth-order tensors. The advantages are that the system is objectively and consistently defined in three ways that each fall into one of three universal classes. Operators within a given class are called conjugate operators such that many familiar and fundamental identities of scalars and second-order tensors are maintained in fourth order; this provides greater insight along with anthropological and pedagogical advantages over current systems, while also revealing new identities and solutions. The relationship between operators of a different class is such that a property of cyclic symmetry arises whereby mixed-class product operators can be cycled around without invalidating an equation. In defining this system, we have considered the following: preservation from identities in zeroth- (scalar) and second-order tensor identities to fourth-order tensor identities; possible permutations of definitions and subsequent logical restrictions; the visual notational consistency throughout the system; and maintenance to legacy definitions and operator symbols. Additionally, we present many new and useful algebraic identities and provide a comparison to some selected contemporary systems used in the literature. We also provide, to complete at least a basic exposition of our proposed system, a set of identities for matrix-equivalent operations, which facilitate programming for numerical computing. This article is designed to be used as a reference work for anyone choosing to adopt this system of tensor operations in continuum mechanics theory involving fourth-order tensors.