As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings.
 
  In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1 0 vs stratum 2 1-2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m
  on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination.
 
  The study included 167 patients (phase Ib, 
  = 7; phase II, 
  = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI) 15.8-38.0] for stratum 1 (
  = 66) and 21.8% (95% CI 14.2-31.1) for stratum 2 (
  = 101). Patients with PD-L1-positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1-negative tumors, particularly in stratum 1 [stratum 1 34.5% (95% CI 17.9-54.3) vs 16.1% (95% CI 5.5-33.7); stratum 2, 24.4% (95% CI 12.9-39.5) vs 18.2% (95% CI 8.2-32.7)].
 
  Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.
 Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC.  https://www.selleckchem.com/products/icec0942-hydrochloride.html  Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.
  Total neoadjuvant treatment (TNT) is a valid strategy for patients with high-risk locally advanced rectal cancer (LARC). Biomarkers of response to TNT are an unmet clinical need. We aimed to determine the value of circulating tumor DNA (ctDNA) to predict tumor response, recurrence, and survival in patients with LARC treated with TNT.
 
  The GEMCAD 1402 was a phase II randomized, multicentric clinical trial that randomized 180 patients with LARC to modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) +/- aflibercept, followed by chemoradiation and surgery. Plasma samples were collected at baseline and after TNT within 48 hours before surgery (presurgery). An ultrasensitive assay that integrates genomic and epigenomic cancer signatures was used to assess ctDNA status. ctDNA results were correlated with variables of local tumor response in the surgery sample, local/systemic recurrence, and survival.
 
  A total of 144 paired plasma samples from 72 patients were included. ctDNA was detectable in 83% of patients at baseline and in 15% following TNT (presurgery). No association was found between ctDNA status and pathologic response. Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival (HR, 4; 
  = 0.033), and shorter overall survival (HR, 23; 
  < 0.0001).
 
  In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.
 In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.
  Several measures recommended by the WHO Framework Convention on Tobacco Control have not been implemented in the European Union, despite changes in the legislation such as the Tobacco Products Directive (TPD). This study aims to understand smokers' and recent quitters' levels of support for tobacco control measures that go beyond the TPD during and after its implementation.
 
  Data from wave 1 (2016, n=6011) and wave 2 (2018, n=6027) of the EUREST-PLUS International Tobacco Control Policy Evaluation Project Six European Countries Survey, a cohort of adult smokers in Germany, Greece, Hungary, Poland, Romania, Spain were used to estimate the level of support for seven different tobacco control measures, overall and by country.
 
  In 2018, the highest support was for implementing measures to further regulate tobacco products (50.5%) and for holding tobacco companies accountable for the harm caused by smoking (48.8%). Additionally, in 2018, 40% of smokers and recent quitters supported a total ban on cigarettes anion with other policies.Substitution for aspartic acid (D) by glycine (G) at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. Here, we report cryo-electron microscopy structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations that differ primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer-effectively increasing the number of functional spikes and enhancing infectivity-and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.Geological evidence shows that ancient Mars had large volumes of liquid water. Models of past hydrogen escape to space, calibrated with observations of the current escape rate, cannot explain the present-day deuterium-to-hydrogen isotope ratio (D/H). We simulated volcanic degassing, atmospheric escape, and crustal hydration on Mars, incorporating observational constraints from spacecraft, rovers, and meteorites. We found that ancient water volumes equivalent to a 100 to 1500 meter global layer are simultaneously compatible with the geological evidence, loss rate estimates, and D/H measurements. In our model, the volume of water participating in the hydrological cycle decreased by 40 to 95% over the Noachian period (~3.7 billion to 4.1 billion years ago), reaching present-day values by ~3.0 billion years ago. Between 30 and 99% of martian water was sequestered through crustal hydration, demonstrating that irreversible chemical weathering can increase the aridity of terrestrial planets.