Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has achieved noteworthy benefit in ...multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumour response. Inhibitors of CTLA4, PD1 or PDL1 administered as single agents have resulted in durable tumour regression in some patients, and combinations of PD1 and CTLA4 inhibitors may enhance antitumour benefit. Numerous additional immunomodulatory pathways as well as inhibitory factors expressed or secreted by myeloid and stromal cells in the tumour microenvironment are potential targets for synergizing with immune checkpoint blockade. Given the breadth of potential targets in the immune system, critical questions to address include which combinations should move forward in development and which patients will benefit from these treatments. This Review discusses the leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Cluster secondary ion mass spectrometry (cluster SIMS) has played a critical role in the characterization of polymeric materials over the last decade, allowing for the ability to obtain spatially ...resolved surface and in-depth molecular information from many polymer systems. With the advent of new molecular sources such as ${\rm C}_{60}^ +$, ${\rm Au}_3^ +$, ${\rm SF}_5^ +$, and ${\rm Bi}_3^ +$, there are considerable increases in secondary ion signal as compared to more conventional atomic beams (Ar⁺, Cs⁺, or Ga⁺). In addition, compositional depth profiling in organic and polymeric systems is now feasible, without the rapid signal decay that is typically observed under atomic bombardment. The premise behind the success of cluster SIMS is that compared to atomic beams, polyatomic beams tend to cause surface-localized damage with rapid sputter removal rates, resulting in a system at equilibrium, where the damage created is rapidly removed before it can accumulate. Though this may be partly true, there are actually much more complex chemistries occurring under polyatomic bombardment of organic and polymeric materials, which need to be considered and discussed to better understand and define the important parameters for successful depth profiling. The following presents a review of the current literature on polymer analysis using cluster beams. This review will focus on the surface and in-depth characterization of polymer samples with cluster sources, but will also discuss the characterization of other relevant organic materials, and basic polymer radiation chemistry.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Purpose Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics ...targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non–small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma. Methods PubMed was searched to identify relevant clinical studies of PD-1/PD-L1–targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic. Findings The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management. Implications This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Model simulations of the 2013 Colorado Front Range floods are performed using 4-km horizontal grid spacing to evaluate the impact of using explicit convection (EC) versus parameterized ...convection (CP) in the model convective physics “gray zone.” Significant differences in heavy precipitation forecasts are found across multiple regions in which heavy rain and high-impact flooding occurred. The relative contribution of CP-generated precipitation to total precipitation suggests that greater CP scheme activity in areas upstream of the Front Range flooding may have led to significant downstream model error.
Heavy convective precipitation simulated by the Kain–Fritsch CP scheme in particular led to an alteration of the low-level moisture flux and moisture transport fields that ultimately prevented the generation of heavy precipitation in downstream areas as observed. An updated, scale-aware version of the Kain–Fritsch scheme is also tested, and decreased model errors both up- and downstream suggest that scale-aware updates yield improvements in the simulation of this event. Comparisons among multiple CP schemes demonstrate that there are model convective physics gray zone considerations that significantly impact the simulation of extreme rainfall in this event.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human ...embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND:Recently, much attention has been directed to femoral component overhang in total knee arthroplasty. The purposes of this study were to describe the prevalence of femoral component ...overhang among men and women after total knee arthroplasty, to identify risk factors for overhang, and to determine whether overhang was associated with postoperative knee pain or decreased range of motion.
METHODS:Femoral component overhang was measured intraoperatively during 437 implantations of the same type of total knee arthroplasty prosthesis. The overhang of metal beyond the bone cut edge was measured in millimeters at the midpoint of ten zones after permanent fixation of the implant. Factors predictive of overhanging fit were identified, and the effect of overhang on postoperative pain and flexion was examined.
RESULTS:Overhang of ≥3 mm occurred in at least one zone among 40% (seventy-one) of 176 knees in men and 68% (177) of 261 knees in women, most frequently in lateral zones 2 (anterior-distal) and 3 (distal). Female sex, shorter height, and larger femoral component size were highly predictive of greater overhang in multivariate models. Femoral component overhang of ≥3 mm in at least one zone was associated with an almost twofold increased risk of knee pain more severe than occasional or mild at two years after surgery (odds ratio, 1.9; 95% confidence interval, 1.1 to 3.3).
CONCLUSIONS:In this series, overhang of the femoral component was highly prevalent, occurring more often and with greater severity in women, and the prevalence and magnitude of overhang increased with larger femoral component sizes among both sexes. Femoral component overhang of ≥3 mm approximately doubles the odds of clinically important knee pain two years after total knee arthroplasty.
LEVEL OF EVIDENCE:Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.
Photocages are light-sensitive chemical protecting groups that provide external control over when, where, and how much of a biological substrate is activated in cells using targeted light ...irradiation. Regrettably, most popular photocages (e.g., o-nitrobenzyl groups) absorb cell-damaging ultraviolet wavelengths. A challenge with achieving longer wavelength bond-breaking photochemistry is that long-wavelength-absorbing chromophores have shorter excited-state lifetimes and diminished excited-state energies. However, here we report the synthesis of a family of BODIPY-derived photocages with tunable absorptions across the visible/near-infrared that release chemical cargo under irradiation. Derivatives with appended styryl groups feature absorptions above 700 nm, yielding photocages cleaved with the highest known wavelengths of light via a direct single-photon-release mechanism. Photorelease with red light is demonstrated in living HeLa cells, Drosophila S2 cells, and bovine GM07373 cells upon ∼5 min irradiation. No cytotoxicity is observed at 20 μM photocage concentration using the trypan blue exclusion assay. Improved B-alkylated derivatives feature improved quantum efficiencies of photorelease ∼20-fold larger, on par with the popular o-nitrobenzyl photocages (εΦ = 50–100 M–1 cm–1), but absorbing red/near-IR light in the biological window instead of UV light.
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IJS, KILJ, NUK, PNG, UL, UM
Circadian rhythms and “clock gene” expression are involved in successful reproductive cycles, mating, and pregnancy. Alterations or disruptions of biological rhythms, as commonly occurs in shift ...work, jet lag, sleep deprivation, or clock gene knock out models, are linked to significant disruptions in reproductive function. These impairments include altered hormonal secretion patterns, reduced conception rates, increased miscarriage rates and an increased risk of breast cancer. Female health may be particularly susceptible to the impact of desynchronizing work schedules as perturbed hormonal rhythms can further influence the expression patterns of clock genes. Estrogen modifies clock gene expression in the uterus, ovaries, and suprachiasmatic nucleus, the site of the primary circadian clock mechanism. Further work investigating clock genes, light exposure, ovarian hormones, and reproductive function will be critical for indentifying how these factors interact to impact health and susceptibility to disease.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Highlights • Involvement in risky behaviors is related to susceptibility to use e-cigarettes in the future. • E-cigarette use is more likely to occur when the use of other substances is present. • ...Non-cigarette tobacco products may be related to susceptibility to cigarette smoking among e-cigarette users.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background Young people are more likely to have experimented with e-cigarettes (e-cigs) compared with older adults. Few studies identify reasons for experimentation/use of e-cigs among young ...people; we sought to discover what drives college students to use e-cigs. Methods Undergraduate students (ages 18–23) at four universities in New York State were surveyed. Among e-cig ever users (n = 429), reasons for use were examined. A multinomial logistic regression model analyzed the relative risk of reasons for using e-cigs among discontinued, current non-daily and current daily e-cig users. Results Using e-cigs for enjoyment was associated with current non-daily (RR = 2.11, 95% CI = 1.18–3.75) and current daily use (RR = 19.1, 95% CI = 3.71–98.54). Non-daily use was related to use because e-cigs are less toxic than cigarettes (RR = 2.80, 95% CI = 1.75–4.50). More daily users reported use to quit smoking compared with either non-daily or discontinued users (53.3% vs. 12.2% and 13.3%, respectively; p < 0.05). Among current users, 72.3% used for enjoyment, compared with 42.9% of discontinued users (p < 0.05). Discussion In contrast to adults, who often report e-cig use to quit smoking, young people are less likely to use for this reason. The exception was daily e-cig users, who often reported use for quitting/reduction of smoking. Rather, college students report usage reasons related to affect (e.g. enjoyment). Overall, enjoyment was reported more often than was use for quitting smoking; affective reasons likely play a role in the popularity of e-cigs and should be considered in future assessments of e-cig users.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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