Although the favourable role of T lymphocyte populations in different tumour types is established, that of B cells is still a matter of debate and needs further clarification. The presence of ...tumour-infiltrating B cells may represent an antibody response against breast tumour antigens. We used immunohistochemistry to investigate the density and localisation of B lymphocytes infiltrating 1470 breast tumours and to identify any prognostic significance and relationship to various clinicopathological factors. Higher numbers of CD20
+
cells were found in the stroma away from the carcinoma (mean 12 cells) compared with either intratumoural or adjacent stromal compartments (mean 1 cell). The majority of tumours showed a diffuse pattern of B cells rather than aggregates. There was a positive correlation between higher numbers of total CD20
+
B cells and higher tumour grade (
r
s
= 0.20,
P
< 0.001), ER and PgR negativity (
P
< 0.001), and basal phenotype (
P
< 0.001) subclass. In univariate survival analysis, higher total number of infiltrating CD20
+
cells, irrespective of location, was associated with significantly better BCSS (
P
= 0.037) and longer DFI (
P
= 0.001). In multivariate analysis, total CD20
+
B cell count (HR = 0.75, 95% CI = 0.58–0.96 for BCSS and HR = 0.72, 95% CI = 0.58–0.89, for DFI), tumour size, nodal stage, grade, vascular invasion, HER-2 status, and total CD8
+
T cell count were independently associated with outcome. This suggests that humoral immunity, in addition to the cell mediated immunity, may be important in breast cancer. This should be considered in breast cancer immunotherapy and vaccine strategies.
Dual blockade of PD-L1 and VEGF has enhanced anticancer immunity through multiple mechanisms and augmented antitumour activity in multiple malignancies. We aimed to assess the efficacy and safety of ...atezolizumab (anti-PD-L1) alone and combined with bevacizumab (anti-VEGF) in patients with unresectable hepatocellular carcinoma.
GO30140 is an open-label, multicentre, multiarm, phase 1b study that enrolled patients at 26 academic centres and community oncology practices in seven countries worldwide. The study included five cohorts, and the two hepatocellular carcinoma cohorts, groups A and F, are described here. Inclusion criteria for these two groups included age 18 years and older; histologically, cytologically, or clinically (per American Association for the Study of Liver Diseases criteria) confirmed unresectable hepatocellular carcinoma that was not amenable to curative treatment; no previous systemic treatment; and Eastern Cooperative Oncology Group performance status of 0 or 1. In group A, all patients received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks. In group F, patients were randomly assigned (1:1) to receive intravenous atezolizumab (1200 mg) plus intravenous bevacizumab (15 mg/kg) every 3 weeks or atezolizumab alone by interactive voice-web response system using permuted block randomisation (block size of two) and stratification factors of geographical region; macrovascular invasion, extrahepatic spread, or both; and baseline α-fetoprotein concentration. Primary endpoints were confirmed objective response rate in all patients who received the combination treatment for group A and progression-free survival in the intention-to-treat population in group F, both assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors version 1.1. In both groups, safety was assessed in all patients who received at least one dose of any study treatment. This study is registered with ClinicalTrials.gov, NCT02715531, and is closed to enrolment.
In group A, 104 patients were enrolled between July 20, 2016, and July 31, 2018, and received atezolizumab plus bevacizumab. With a median follow-up of 12·4 months (IQR 8·0–16·2), 37 (36%; 95% CI 26–46) of 104 patients had a confirmed objective response. The most common grade 3–4 treatment-related adverse events were hypertension (13 13%) and proteinuria (seven 7%). Treatment-related serious adverse events occurred in 25 (24%) patients and treatment-related deaths in three (3%) patients (abnormal hepatic function, hepatic cirrhosis, and pneumonitis). In group F, 119 patients were enrolled and randomly assigned (60 to atezolizumab plus bevacizumab; 59 to atezolizumab monotherapy) between May 18, 2018, and March 7, 2019. With a median follow-up of 6·6 months (IQR 5·5–8·5) for the atezolizumab plus bevacizumab group and 6·7 months (4·2–8·2) for the atezolizumab monotherapy group, median progression-free survival was 5·6 months (95% CI 3·6–7·4) versus 3·4 months (1·9–5·2; hazard ratio 0·55; 80% CI 0·40–0·74; p=0·011). The most common grade 3–4 treatment-related adverse events in group F were hypertension (in three 5% patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group) and proteinuria (in two 3% patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group). Treatment-related serious adverse events occurred in seven (12%) patients in the atezolizumab plus bevacizumab group and two (3%) patients in the atezolizumab monotherapy group. There were no treatment-related deaths.
Our study shows longer progression-free survival with a combination of atezolizumab plus bevacizumab than with atezolizumab alone in patients with unresectable hepatocellular carcinoma not previously treated with systemic therapy. Therefore, atezolizumab plus bevacizumab might become a promising treatment option for these patients. This combination is being compared with standard-of-care sorafenib in a phase 3 trial.
F Hoffmann-La Roche/Genentech.
Peptide therapeutics is a promising field for emerging anti-cancer agents. Benefits include the ease and rapid synthesis of peptides and capacity for modifications. An existing and vast knowledge ...base of protein structure and function can be exploited for novel peptide design. Current research focuses on developing peptides that can (1) serve as tumor targeting moieties and (2) permeabilize membranes with cytotoxic consequences. A survey of recent findings reveals significant trends. Amphiphilic peptides with clusters of hydrophobic and cationic residues are features of anti-microbial peptides that confer the ability to eradicate microbes and show considerable anti-cancer toxicity. Peptides that assemble and form pores can disrupt cell or organelle membranes and cause apoptotic or necrotic death. Cell permeable and tumor-homing peptides can carry biologically active cargo to tumors or tumor vasculature. The challenge lies in developing the clinical application of therapeutic peptides. Improving delivery to tumors, minimizing non-specific toxic effects and discerning pharmacokinetic properties are high among the needs to produce a powerful therapeutic peptide for cancer treatment.
We report a new synthesis of best estimates of the inputs of fixed nitrogen to the world ocean via atmospheric deposition and compare this to fluvial inputs and dinitrogen fixation. We evaluate the ...scale of human perturbation of these fluxes. Fluvial inputs dominate inputs to the continental shelf, and we estimate that about 75% of this fluvial nitrogen escapes from the shelf to the open ocean. Biological dinitrogen fixation is the main external source of nitrogen to the open ocean, i.e., beyond the continental shelf. Atmospheric deposition is the primary mechanism by which land‐based nitrogen inputs, and hence human perturbations of the nitrogen cycle, reach the open ocean. We estimate that anthropogenic inputs are currently leading to an increase in overall ocean carbon sequestration of ~0.4% (equivalent to an uptake of 0.15 Pg C yr−1 and less than the Duce et al. (2008) estimate). The resulting reduction in climate change forcing from this ocean CO2 uptake is offset to a small extent by an increase in ocean N2O emissions. We identify four important feedbacks in the ocean atmosphere nitrogen system that need to be better quantified to improve our understanding of the perturbation of ocean biogeochemistry by atmospheric nitrogen inputs. These feedbacks are recycling of (1) ammonia and (2) organic nitrogen from the ocean to the atmosphere and back, (3) the suppression of nitrogen fixation by increased nitrogen concentrations in surface waters from atmospheric deposition, and (4) increased loss of nitrogen from the ocean by denitrification due to increased productivity stimulated by atmospheric inputs.
Key Points
A new estimate of total atmospheric fixed nitrogen inputs to the ocean (39 Tg N yr−1) and its spatial distribution is presented
The effects of atmospheric deposition on the oceans are estimated as an increase of productivity equivalent to 0.15 Pg C yr−1
Four key uncertainties in these estimates are identified
We show that in a perpendicularly magnetized Pt/Co bilayer the spin-Hall effect (SHE) in Pt can produce a spin torque strong enough to efficiently rotate and switch the Co magnetization. We calculate ...the phase diagram of switching driven by this torque, finding quantitative agreement with experiments. When optimized, the SHE torque can enable memory and logic devices with similar critical currents and improved reliability compared to conventional spin-torque switching. We suggest that the SHE torque also affects current-driven magnetic domain wall motion in Pt/ferromagnet bilayers.
Summary
Background
Anti‐tumour necrosis factor‐alpha agents (anti‐TNF) are effective therapies for the treatment of Crohn's disease (CD), but their comparative efficacy is unknown.
Aim
To perform a ...network meta‐analysis comparing the efficacy of anti‐TNF therapies in CD.
Methods
After screening 506 studies, reviewers extracted information on 10 studies. Traditional meta‐analysis (TMA) was used to compare each anti‐TNF agent to placebo. Bayesian network meta‐analysis (NMA) was performed to compare the effects of anti‐TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated.
Results
Compared to placebo, TMA revealed that anti‐TNF agents result in a higher likelihood of induction of remission and response (RR: 1.66, 95% CI: 1.17–2.36 and RR: 1.43, 95% CI: 1.17–1.73, respectively) as well as maintenance of remission and response (RR: 1.78, 95% CI: 1.51–2.09 and RR: 1.68, 95% CI: 1.46–1.93, respectively). NMA found nonsignificant trends between infliximab and adalimumab or certolizumab pegol. Among subcutaneous therapies, NMA demonstrated superiority of adalimumab to certolizumab pegol for induction of remission (RR: 2.93, 95% CrI: 1.21–7.75). Sample size calculations suggest that adequately powered head‐to‐head comparative efficacy trials would require greater than 3000 patients.
Conclusions
All anti‐TNF agents are effective for induction and maintenance of response and remission in the treatment of CD. Although adalimumab is superior to certolizumab pegol for induction of remission, there is no evidence of clinical superiority among anti‐TNF agents. Head‐to‐head trials among the anti‐TNF agents are impractical in terms of size and cost.
Comprehensive multisystem clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to ...revise the instrument. The previous version of BVAS has been revised, according to usage and reviewed by an expert committee.
To modify and validate version 3 of the BVAS in patients with systemic vasculitis.
The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis.
The number of items was reduced from 66 to 56. The subscores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman's r(s) = 0.66, 95% CI 0.59 to 0.72), BVAS1 of version 2 (r(s) = 0.94, 95% CI 0.92 to 0.96), BVAS2 of version 2 in patients with persistent disease (r(s) = 0.60, 95% CI 0.21 to 0.83), C-reactive protein levels (r(s) = 0.43, 95% CI 0.31 to 0.54), physician's global assessment (r(s) = 0.91, 95% CI 0.89 to 0.93) and vasculitis activity index (r(s) = 0.88, 95% CI 0.86 to 0.91). The intraclass correlation coefficients for reproducibility and repeatability were 0.96 (95% CI 0.95 to 0.97) and 0.96 (95% CI 0.92 to 0.97), respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15 to 19) units (p<0.001, paired t test).
BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and C-reactive protein. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.
Collagen is the primary component of the extracellular matrix in the human body. It has proved challenging to fabricate collagen scaffolds capable of replicating the structure and function of tissues ...and organs. We present a method to 3D-bioprint collagen using freeform reversible embedding of suspended hydrogels (FRESH) to engineer components of the human heart at various scales, from capillaries to the full organ. Control of pH-driven gelation provides 20-micrometer filament resolution, a porous microstructure that enables rapid cellular infiltration and microvascularization, and mechanical strength for fabrication and perfusion of multiscale vasculature and tri-leaflet valves. We found that FRESH 3D-bioprinted hearts accurately reproduce patient-specific anatomical structure as determined by micro-computed tomography. Cardiac ventricles printed with human cardiomyocytes showed synchronized contractions, directional action potential propagation, and wall thickening up to 14% during peak systole.
Estrogen is a potent steroid with pleiotropic effects, which have yet to be fully elucidated. Estrogen has both nuclear and non-nuclear effects. The rapid response to estrogen, which involves a ...membrane associated estrogen receptor(ER) and is protective, involves signaling through PI3K, Akt, and ERK 1/2. The nuclear response is much slower, as the ER-estrogen complex moves to the nucleus, where it functions as a transcription factor, both activating and repressing gene expression. Several different ERs regulate the specificity of response to estrogen, and appear to have specific effects in cardiac remodeling and the response to injury. However, much remains to be understood about the selectivity of these receptors and their specific effects on gene expression. Basic studies have demonstrated that estrogen treatment prevents apoptosis and necrosis of cardiac and endothelial cells. Estrogen also attenuates pathologic cardiac hypertrophy. Estrogen may have great benefit in aging as an anti-inflammatory agent. However, clinical investigations of estrogen have had mixed results, and not shown the clear-cut benefit of more basic investigations. This can be explained in part by differences in study design: in basic studies estrogen treatment was used immediately or shortly after ovariectomy, while in some key clinical trials, estrogen was given years after menopause. Further basic research into the underlying molecular mechanisms of estrogen's actions is essential to provide a better comprehension of the many properties of this powerful hormone.
PDF
