The unprecedented benefits of immunotherapy in advanced malignancies have resulted in increased interests in exploiting immune stimulatory agents in earlier-stage solid tumors in the neoadjuvant ...setting. However, systemic delivery of immunotherapies may cause severe immune-related side-effects and hamper the development of combination treatments. Intratumoral delivery of neoadjuvant immunotherapy provides a promising strategy in harnessing the power of immunotherapy while minimizing off-target toxicities. The direct injection of immune stimulating agents into the tumor primes the local tumor-specific immunity to generate a systemic, durable clinical response. Intratumoral immunotherapy is a highly active area of investigation resulting in a plethora of agents, for example, immune receptor agonists, non-oncolytic and oncolytic viral therapies, being tested in preclinical and clinical settings. Currently, more than 20 neoadjuvant clinical trials exploring distinct intratumoral immune stimulatory agents and their combinations are ongoing. Practical considerations, including appropriate timing and optimal local delivery of immune stimulatory agents play an important role in safety and efficacy of this approach. Here, we discuss promising approaches in drug delivery technologies and opportunity for combining intratumoral immunotherapy with other cancer treatments and summarize the recent preclinical and clinical evidences that highlighted its promise as a part of routine oncologic care.
Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy ...with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.
In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m2 subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597.
Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6–21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3–not estimable) with venetoclax versus 11·5 months (9·6–15·0) with placebo (hazard ratio HR 0·63 95% CI 0·44–0·90; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 18% of 193 patients in the venetoclax group vs seven 7% of 96 patients in the placebo group), pneumonia (30 16% vs nine 9%), thrombocytopenia (28 15% vs 29 30%), anaemia (28 15% vs 14 15%), and diarrhoea (28 15% vs 11 11%). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related.
The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option.
AbbVie and Genentech.
•Critical sparging rate and optimal sparging strategy were determined in a SAnMBR.•Alternating sparging reduced membrane fouling by 150% compared to constant sparging.•Fractions of supracolloids, ...SMPs, and EPS decreased with reduced sparging.•High MW SMPs (>1522kDa) rejected by membrane, low MW SMPs (<500kDa) in permeate.•Foulant SMPs came from both the reactor supernatant and biomass on the membrane.
Biogas sparging is considered to be an effective way to control membrane fouling in an anaerobic membrane bioreactor, but is primarily used with a constant gas flow. This paper examined whether different gassing strategies could lead to better fouling control, and tried to understand the correlation between sludge properties and the fouling layer by disaggregating them into supracolloidal (1–5µm), colloidal (0.45µm–1µm) and solute (<0.45µm) fractions. This study found that the “critical constant sparging rate” was 6L per minute (LPM) at a flux of 26L per square meter per hour (LMH). However, a sparging strategy of 3LPM for 30s alternating with 5LPM for 30s (Alter 3/5) reduced membrane fouling by 150% compared with a constant 4LPM strategy. The viscosity, colloid and floc sizes of the suspended sludge increased with decreasing sparging rate, while the concentration of supracolloidal particles, soluble microbial products (SMPs) proteins and carbohydrates, and extracellular polymeric substances (EPS) decreased with decreasing sparging rate. Colloids were the major foulants above 2LPM, while HPLC-SEC analysis showed that one main SMP fraction was above 1522kDa, and the other between 72 and 500kDa. The high MW compounds accumulated on the membrane, while the later permeated through into the effluent. With the Alt 3/5 strategy, SMPs were the primary foulants, and the particle sizes were a lot smaller than in the supernatant. The foulant SMPs not only originated from the reactor supernatant, but were also produced by biomass in the membrane fouling layer. Chemical analyses reflected the effect of different sparging rates on sludge properties, the production of colloids, SMPs and EPS, and the foulant components.
The Low-Profile Visualized Intraluminal Support (LVIS) stent is a new device recently introduced for the treatment of wide-neck intracranial aneurysms. This single-center study presents the authors' ...preliminary experience using the LVIS stent to treat saccular aneurysms with parent arteries smaller than 2.5 mm.
Aneurysms with a LVIS stent used in a small parent vessel (<2.5 mm in diameter) between October 2014 and April 2016 were included. Procedure-related complications, angiographic results, clinical outcomes, and midterm follow-up data were analyzed retrospectively.
A total of 22 patients was studied, including 5 ruptured and 17 unruptured aneurysms. Most of the aneurysms were located in the anterior circulation (90.9%). Stent placement in the parent arteries measuring 1.7-2.4 mm in diameter (mean, 2.1 mm) was successful in 100% of cases. Procedure-related complication developed in 1 patient (4.5%) who presented with aneurysm rupture. No permanent morbidity and mortality occurred. Immediate angiographic outcome showed complete occlusion in 8 aneurysms (36.4%), neck residual in 8 (36.4%), and residual aneurysm in 6 (27.3%). All patients underwent angiographic follow-up at a mean of 8.3 months, which revealed complete occlusion in 18 (81.8%) patients, neck remnant in 3 (13.6%), and residual sac in 1 (4.5%). No recanalization of the target aneurysm was observed. There was 1 case with asymptomatic in-stent stenosis.
Our preliminary results show that the deployment of LVIS stents in small vessels is feasible, safe, and effective in the midterm. Larger studies with long-term follow-up are needed to validate our promising results.
This study was conducted to evaluate sexual function in adult survivors of childhood cancers and investigate possible relationships between sexual function and quality of life, as measured by general ...well-being, self-esteem, body image, and depressive symptoms.
This cross-sectional survey was performed in our centre from 14 August 2015 to 8 September 2017. Adult patients who had a history of childhood cancers, and who were disease-free for >3 years, were approached for the study during clinical follow-up. Clinical information was collected from medical records. Self-administered questionnaires regarding quality of life and sexual functioning were given to the patients and resulting data were analysed.
Two hundred patients agreed to participate in the study. The overall response rate was 64.8%. Ninety-one (45.5%) patients were women, and the mean age was 25.4 ± 5.57 years. The overall sexual functioning score was 28.3 ± 20.09. Forty-eight (24.0%) patients reported at least one sexual problem. Among patients who reported no sexual problems, more had haematological cancers (P=0.009), fewer underwent surgery (P=0.004), fewer underwent surgery with external effects (P=0.032), and fewer were regular social drinkers (P=0.013); additionally, they had a higher mean Rosenberg self-esteem scale score (P=0.010), lower mean body image scale score (P=0.008), and lower mean Patient Health Questionnaire score (P=0.001).
Aspects of life beyond disease condition and physical function should be considered in adult survivors of childhood cancers. Appropriate referral and intervention should be initiated for these patients when necessary.
Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data ...analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
Recognition of histone covalent modifications by chromatin-binding protein modules (“readers”) constitutes a major mechanism for epigenetic regulation, typified by bromodomains that bind ...acetyllysine. Non-acetyl histone lysine acylations (e.g., crotonylation, butyrylation, propionylation) have been recently identified, but readers that prefer these acylations have not been characterized. Here we report that the AF9 YEATS domain displays selectively higher binding affinity for crotonyllysine over acetyllysine. Structural studies revealed an extended aromatic sandwiching cage with crotonyl specificity arising from π-aromatic and hydrophobic interactions between crotonyl and aromatic rings. These features are conserved among the YEATS, but not the bromodomains. Using a cell-based model, we showed that AF9 co-localizes with crotonylated histone H3 and positively regulates gene expression in a YEATS domain-dependent manner. Our studies define the evolutionarily conserved YEATS domain as a family of crotonyllysine readers and specifically demonstrate that the YEATS domain of AF9 directly links histone crotonylation to active transcription.
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•The YEATS domains constitute a family of histone crotonylation reader modules•AF9 YEATS recognizes histone crotonylation via an extended aromatic sandwich pocket•Bromodomains do not exhibit YEATS-like preference for crotonyllysine•Histone crotonylation potentiates gene expression in an AF9 YEATS-dependent manner
Li et al. demonstrate that the YEATS domain has an expanded acyl-binding repertoire with highest preference for crotonyllysine. The AF9 YEATS-crotonyllysine interaction is critical for histone crotonylation-dependent gene activation in the context of the inflammatory response.
Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. ...In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.
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•SARS-CoV-2 RBD is immunodominant and accounts for 90% of serum neutralizing activity•RBD antibodies decline with a half-life of ∼50 days, but their avidity increases•Structural definition of a SARS-CoV-2 RBD antigenic map using monoclonal antibodies•ACE2-binding site dominates SARS-CoV-2 polyclonal neutralizing antibody responses
Serological analyses of ∼650 SARS-CoV-2-exposed individuals show that 90% of the serum or plasma neutralizing activity targets the virus receptor-binding domain, with structural insights revealing how distinct types of neutralizing antibodies targeting the ACE2-binding site dominate the immune response against SARS-CoV-2 spike.
The pseudostratified epithelium of the lung contains ciliated and secretory luminal cells and basal stem/progenitor cells. To identify signals controlling basal cell behavior we screened factors that ...alter their self-renewal and differentiation in a clonal organoid (tracheosphere) assay. This revealed that inhibitors of the canonical BMP signaling pathway promote proliferation but do not affect lineage choice, whereas exogenous Bmp4 inhibits proliferation and differentiation. We therefore followed changes in BMP pathway components in vivo in the mouse trachea during epithelial regeneration from basal cells after injury. The findings suggest that BMP signaling normally constrains proliferation at steady state and this brake is released transiently during repair by the upregulation of endogenous BMP antagonists. Early in repair, the packing of epithelial cells along the basal lamina increases, but density is later restored by active extrusion of apoptotic cells. Systemic administration of the BMP antagonist LDN-193189 during repair initially increases epithelial cell number but, following the shedding phase, normal density is restored. Taken together, these results reveal crucial roles for both BMP signaling and cell shedding in homeostasis of the respiratory epithelium.
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