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Executive summary 50 years after a noble but flawed attempt to eradicate malaria in the mid-20th century, the global malaria community is once again seriously considering eradication. Momentum towards eradication has been building for decades, and more than half of the world’s countries are now malaria free. Since 2000, a surge of global progress has occurred, facilitated by the roll-out of new technologies and the substantial growth in political and financial commitment by countries, regions, and their global partners. Annual domestic and international spending on malaria increased from roughly US$1·5 billion in 2000 to $4·3 billion in 2016. Simultaneously, the number of countries with endemic malaria dropped from 106 to 86, the worldwide annual incidence rate of malaria declined by 36%, and the annual death rate declined by 60%. Inspired by these outstanding achievements, and troubled by a stagnation in progress that saw 55 countries report an increase in cases between 2015 and 2017, the Lancet Commission on Malaria Eradication (the Commission) was convened to consider whether malaria eradication is feasible, affordable, and worthwhile. In this report of the Commission, we synthesise existing evidence and new epidemiological and financial analyses to show that malaria eradication by 2050 is a bold but attainable goal, and a necessary one given the neverending struggle against drug and insecticide resistance and the social and economic costs associated with a failure to eradicate.

ObjectiveThe prognostic significance of isolated tumor cells (≤0.2 mm) in sentinel lymph nodes (SLNs) of endometrial cancer patients is still unclear. Our aim was to assess the prognostic value of isolated tumor cells in patients with low risk endometrial cancer who underwent SLN biopsy and did not receive adjuvant therapy. Outcomes were compared with node negative patients.MethodsPatients with SLNs–isolated tumor cells between 2013 and 2019 were identified from 15 centers worldwide, while SLN negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018. Only low risk patients (stage IA, endometrioid histology, grade 1 or 2) who did not receive any adjuvant therapy were included. Primary outcomes were recurrence free, non-vaginal recurrence free, and overall survival, evaluated with Kaplan–Meier methods.Results494 patients (42 isolated tumor cells and 452 node negative) were included. There were 21 (4.3%) recurrences (5 SLNs–isolated tumor cells, 16 node negative); recurrence was vaginal in six patients (1 isolated tumor cells, 5 node negative), and non-vaginal in 15 (4 isolated tumor cells, 11 node negative). Median follow-up among those without recurrence was 2.3 years (interquartile range (IQR) 1.1–3.0) and 2.6 years (IQR 0.6–4.2) in the SLN–isolated tumor cell and node negative patients, respectively. The presence of SLNs-isolated tumor cells, lymphovascular space invasion, and International Federation of Obstetrics and Gynecology (FIGO) grade 2 were significant risk factors for recurrence on univariate analysis. SLN–isolated tumor cell patients had worse recurrence free survival (p<0.01) and non-vaginal recurrence free survival (p<0.01) compared with node negative patients. Similar results were observed in the subgroup of patients without lymphovascular space invasion (n=480). There was no difference in overall survival between the two cohorts in the full sample and the subset excluding patients with lymphovascular space invasion.ConclusionsPatients with SLNs–isolated tumor cells and low risk profile, without adjuvant therapy, had a significantly worse recurrence free survival compared with node negative patients with similar risk factors, after adjusting for grade and excluding patients with lymphovascular space invasion. However, the presence of SLNs–isolated tumor cells was not associated with worse overall survival.

Dysregulated glutamatergic neurotransmission has been strongly implicated in the pathophysiology of schizophrenia (SCZ). Recently, presynaptic modulation of glutamate transmission has been shown to have therapeutic promise. We asked whether genetic knockdown of glutaminase (gene GLS1 ) to reduce glutamatergic transmission presynaptically by slowing the recycling of glutamine to glutamate, would produce a phenotype relevant to SCZ and its treatment. GLS1 heterozygous (GLS1 het) mice showed about a 50% global reduction in glutaminase activity, and a modest reduction in glutamate levels in brain regions relevant to SCZ pathophysiology, but displayed neither general behavioral abnormalities nor SCZ-associated phenotypes. Functional imaging, measuring regional cerebral blood volume, showed hippocampal hypometabolism mainly in the CA1 subregion and subiculum, the inverse of recent clinical imaging findings in prodromal and SCZ patients. GLS1 het mice were less sensitive to the behavioral stimulating effects of amphetamine, showed a reduction in amphetamine-induced striatal dopamine release and in ketamine-induced frontal cortical activation, suggesting that GLS1 het mice are resistant to the effects of these pro-psychotic challenges. Moreover, GLS1 het mice showed clozapine-like potentiation of latent inhibition, suggesting that reduction in glutaminase has antipsychotic-like properties. These observations provide further support for the pivotal role of altered glutamatergic synaptic transmission in the pathophysiology of SCZ, and suggest that presynaptic modulation of the glutamine–glutamate pathway through glutaminase inhibition may provide a new direction for the pharmacotherapy of SCZ.

Introduction/BackgroundThe clinical impact of isolated tumor cells (ITC) (≤0.2 mm) in sentinel lymph nodes (SLN) of endometrial cancer (EC) is unclear. This study compared the recurrence-free survival (RFS) of intermediate-risk EC patients who underwent SLN biopsy and were node-negative vs. those who had ITC.MethodologyPatients with SLN-ITC, between 2012 and 2019, were identified from 21 centers worldwide, while SLN-node-negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018 and served as comparing group. Only patients with uterine-confined EC and intermediate-risk factors [grade 1 or 2 endometrioid and myometrial invasion (MI) ≥50%; grade 3 endometrioid and MI <50%; non-endometrioid without MI] were included. Adjuvant therapy (ATx) included vaginal brachytherapy (VB), external beam radiation and/or chemotherapy (EBRT±CHT). The primary outcome was non-vaginal recurrence (hematogenous, peritoneal or lymphatic).ResultsOf 200 patients included, 74 had ITC and 126 were node-negative. Sixteen patients had a non-vaginal recurrence and the median follow-up for patients without recurrence was 2.9 (IQR, 1.8–3.8) and 2.8 (0.8–4.4) years for the two groups, respectively. Among the 162 patients with ATx (VB only=112; EBRT±CHT=50), there was no significant difference in non-vaginal RFS between ITC vs. node-negative patients [p=0.34; 4-year RFS 84.1% (95% CI, 72.1–98.1%) vs. 91.5% (95% CI, 84.1–99.4%) for 61 ITC vs. 101 node-negative]. However, we observed worse non-vaginal RFS in the subgroup of 32 patients with concurrent ITC and LVSI (p=0.006, figure 1). In particular, the 4-year RFS was 64.6% (95% CI, 43.2–96.8%) in this subgroup compared to 93.3% (95% CI, 81.5–100%) and 91.7% (95% CI, 83.9–100%) for the node-negative patients with and without LVSI, respectively. There were no recurrences among 29 patients with ITC and no LVSI.Abstract 2022-RA-998-ESGO Figure 1Non-vaginal recurrence-free survival among patients with intermediate risk factors who received adjuvant therapy, according to nodal status and LVSIConclusionOur results on intermediate-risk EC, who received ATx, suggest that the simultaneous presence of ITC and LVSI is associated with a poorer prognosis. Further studies are warranted.

Introduction/BackgroundThe prognostic value of isolated tumor cells (ITC) (≤0.2 mm) in sentinel lymph nodes (SLN) of patients with endometrial cancer (EC) is still unclear. This study compared the recurrence-free survival (RFS) of low-risk EC patients who received no adjuvant therapy, who underwent a SLN biopsy and were node-negative vs. those who had ITC.MethodologyPatients with SLN-ITC, between 2012 and 2019, were identified from 21 centers worldwide, while SLN-node-negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018 and served as a comparing group. Only patients with stage IA endometrioid histology, and low-risk profile (grade 1 or 2 endometroid and myometrial infiltration <50%) who did not receive adjuvant therapy were included. The primary outcome was non-vaginal recurrence (peritoneal, hematogenous, and lymphatic).ResultsA total of 494 patients (42 ITC and 452 node-negative) were included. There were 15 recurrences and the overall median follow-up for patients without recurrence was 2.2 (IQR 1.1–3.0) years for the ITC group and 2.6 (IQR 0.6–4.2) years for the node-negative group. The presence of SLN-ITC (HR, 5.66; 95% CI, 1.76–18.23), LVSI (HR, 10.66 95% CI, 2.27–50.04) and grade 2 (HR, 3.16; 95% CI, 1.14–8.75) were significant risk factors for non-vaginal recurrence at univariate analysis. Non-vaginal RFS was significantly poorer for the ITC group (vs. node-negative) [p=0.001, figure 1, 4-year RFS: 88.2% (95% CI, 77.8–100) vs 96.9% (95% CI, 94.5–99.3)]. Furthermore, among those without LVSI (N=480), the presence of SLN-ITC (adjusted HR, 4.47; 95% CI, 1.21–16.60) was significantly associated with non-vaginal recurrence after adjusting for grade.Abstract 2022-RA-1052-ESGO Figure 1Non-vaginal recurrence-free survival among patients with low-risk factors who received no adjuvant therapy, according to nodal statusConclusionPatients with SLN-ITC and a low-risk profile who received no adjuvant therapy had a worse prognosis than node-negative patients with similar risk factors after considering grade and LVSI. Longer follow-up is needed to confirm this finding.

The prognostic significance of isolated tumor cells (≤0.2 mm) in sentinel lymph nodes (SLNs) of endometrial cancer patients is still unclear. Our aim was to assess the prognostic value of isolated tumor cells in patients with low risk endometrial cancer who underwent SLN biopsy and did not receive adjuvant therapy. Outcomes were compared with node negative patients. Patients with SLNs-isolated tumor cells between 2013 and 2019 were identified from 15 centers worldwide, while SLN negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018. Only low risk patients (stage IA, endometrioid histology, grade 1 or 2) who did not receive any adjuvant therapy were included. Primary outcomes were recurrence free, non-vaginal recurrence free, and overall survival, evaluated with Kaplan-Meier methods. 494 patients (42 isolated tumor cells and 452 node negative) were included. There were 21 (4.3%) recurrences (5 SLNs-isolated tumor cells, 16 node negative); recurrence was vaginal in six patients (1 isolated tumor cells, 5 node negative), and non-vaginal in 15 (4 isolated tumor cells, 11 node negative). Median follow-up among those without recurrence was 2.3 years (interquartile range (IQR) 1.1-3.0) and 2.6 years (IQR 0.6-4.2) in the SLN-isolated tumor cell and node negative patients, respectively. The presence of SLNs-isolated tumor cells, lymphovascular space invasion, and International Federation of Obstetrics and Gynecology (FIGO) grade 2 were significant risk factors for recurrence on univariate analysis. SLN-isolated tumor cell patients had worse recurrence free survival (p<0.01) and non-vaginal recurrence free survival (p<0.01) compared with node negative patients. Similar results were observed in the subgroup of patients without lymphovascular space invasion (n=480). There was no difference in overall survival between the two cohorts in the full sample and the subset excluding patients with lymphovascular space invasion. Patients with SLNs-isolated tumor cells and low risk profile, without adjuvant therapy, had a significantly worse recurrence free survival compared with node negative patients with similar risk factors, after adjusting for grade and excluding patients with lymphovascular space invasion. However, the presence of SLNs-isolated tumor cells was not associated with worse overall survival.

A study suggests that the failure to activate cyclin E-Cdk2 kinase activity in senescent cells may account for the inability of these cells to phosporylate the retinoblastoma protein in late G1 phase, which in turn may block the expression of late G1 genes such as cyclin A that are required for entry into S phase.

Senescent human diploid fibroblasts are unable to enter S phase in response to mitogenic stimulation. One of the key deficiencies in mitogen-stimulated senescent cells is their failure to phosphorylate the retinoblastoma protein, which acts as an inhibitor of entry into S phase in its unphosphorylated form. Recent data suggest that cyclin-dependent kinases (Cdks) regulated by G1 cyclins (D type and E) are responsible for the primary phosphorylation of the retinoblastoma protein prior to the G1/S boundary. Surprisingly, we found 10- to 15-fold higher constitutive amounts of both cyclin E and cyclin D1 in senescent cells compared to quiescent early-passage cells. Nevertheless, cyclin E-associated kinase activity in senescent cells was very low and did not increase significantly upon mitogenic stimulation even though cyclin E-Cdk2 complexes were abundant. In contrast to early-passage cells in late G1 phase, senescent cells contained mainly underphosphorylated cyclin E and proportionally more unphosphorylated and inactive Cdk2, perhaps accounting for the low kinase activity. We also show that a majority of the Cdk2 in senescent cells, but not in early-passage cells, was complexed with cyclin D1. Cyclin D1-Cdk2 complexes, severalfold enriched in senescent cells, contained exclusively unphosphorylated Cdk2. Amounts of cyclin A, which ordinarily accumulates in S and G2 phases, were extremely low in stimulated senescent cells. We suggest that the failure to activate cyclin E-Cdk2 kinase activity in senescent cells may account for the inability of these cells to phosphorylate the retinoblastoma protein in late G1 phase, which in turn may block the expression of late G1 genes such as cyclin A that are required for entry into S phase.

ABSTRACT Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome. Competing Interest Statement Xiaodong Wang is employee of Cipher Gene, Ltd. Richard E. Person, Kristin G. Monaghan, Amy Crunk, Jennifer Keller-Ramey, Adi Reich and Houda Zghal Elloumi are employees of GeneDx, Inc. The other authors declare no competing interest. Footnotes * ↵* shared first author