Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic ...melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14
CD16
HLA-DR
monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support.
Intracellular bacteria have developed numerous strategies to hijack host vesicular trafficking pathways to form their unique replicative niches. To promote intracellular replication, the bacteria ...must interact with host organelles and modulate host signaling pathways to acquire nutrients and membrane for the growing parasitophorous vacuole all while suppressing activation of the immune response. To facilitate host cell subversion, bacterial pathogens use specialized secretion systems to deliver bacterial virulence factors, termed effectors, into the host cell that mimic, agonize, and/or antagonize the function of host proteins. In this review we will discuss how bacterial effector proteins from
serovar Typhimurium,
, and
manipulate the endocytic and secretory pathways. Understanding how bacterial effector proteins manipulate host processes not only gives us keen insight into bacterial pathogenesis, but also enhances our understanding of how eukaryotic membrane trafficking is regulated.
Determining the brain perfusion is an important task for diagnosis of vascular diseases such as occlusions and intracerebral haemorrhage. Even after successful diagnosis, there is a high risk of ...restenosis or rebleeding such that patients need intense attention in the days after treatment. Within this work, we present a diagnostic tomographic imager that allows access to brain perfusion quantitatively in short intervals. The device is based on the magnetic particle imaging technology and is designed for human scale. It is highly sensitive and allows the detection of an iron concentration of 263 pmol
ml
, which is one of the lowest iron concentrations imaged by MPI so far. The imager is self-shielded and can be used in unshielded environments such as intensive care units. In combination with the low technical requirements this opens up a variety of medical applications and would allow monitoring of stroke on intensive care units.
NT-proBNP seems to be affected more by worsening renal function than BNP. Besides diminished renal clearance, higher prevalence of concomitant left ventricular alterations such as left ventricular ...hypertrophy, diastolic and systolic dysfunction as well as fluid overload might contribute to elevated BNP and NT-proBNP concentrations. Role of BNP and NT-proBNP in clinical routine: key points B-type natriuretic peptide (BNP) and NT-proBNP are reliable biomarkers, reflecting myocardial stress caused by various cardiovascular diseases Both markers are stable in whole blood and can be measured in clinical routine using fully automated commercially available assays The diagnostic performance of BNP and NT-proBNP is comparable and there is no meaningful difference between the two The particular strength of BNP and NT-proBNP is to rule out heart failure in patients with shortness of breath in the emergency department Both markers provide prognostic information in patients with heart failure, coronary artery disease, and valvular heart disease Additional references appear on the Heart website- http://www.heartjnl.com/supplemental
Stereotactic body radiation therapy (SBRT) provides high rates of local control (LC) and margin-negative (R0) resections for locally advanced pancreatic cancer (LAPC) and borderline resectable ...pancreatic cancer (BRPC), respectively, with minimal toxicity.
A single-institution retrospective review was performed for patients with nonmetastatic pancreatic cancer treated with induction chemotherapy followed by SBRT. SBRT was delivered over 5 consecutive fractions using a dose painting technique including 7-10 Gy/fraction to the region of vessel abutment or encasement and 5-6 Gy/fraction to the remainder of the tumor. Restaging scans were performed at 4 weeks, and resectable patients were considered for resection. The primary endpoints were overall survival (OS) and progression-free survival (PFS).
Seventy-three patients were evaluated, with a median follow-up time of 10.5 months. Median doses of 35 Gy and 25 Gy were delivered to the region of vessel involvement and the remainder of the tumor, respectively. Thirty-two BRPC patients (56.1%) underwent surgery, with 31 undergoing an R0 resection (96.9%). The median OS, 1-year OS, median PFS, and 1-year PFS for BRPC versus LAPC patients was 16.4 months versus 15 months, 72.2% versus 68.1%, 9.7 versus 9.8 months, and 42.8% versus 41%, respectively (all P>.10). BRPC patients who underwent R0 resection had improved median OS (19.3 vs 12.3 months; P=.03), 1-year OS (84.2% vs 58.3%; P=.03), and 1-year PFS (56.5% vs 25.0%; P<.0001), respectively, compared with all nonsurgical patients. The 1-year LC in nonsurgical patients was 81%. We did not observe acute grade ≥3 toxicity, and late grade ≥3 toxicity was minimal (5.3%).
SBRT safely facilitates margin-negative resection in patients with BRPC pancreatic cancer while maintaining a high rate of LC in unresectable patients. These data support the expanded implementation of SBRT for pancreatic cancer.
Previous studies demonstrated the relevance of focal lesions (FL) in whole-body magnetic resonance imaging (wb-MRI) at the initial workup of patients with smoldering multiple myeloma (SMM). The aim ...of this study was to assess the effects of longitudinal wb-MRIs on progression into multiple myeloma (MM). Sixty-three patients with SMM were analyzed who received at least two wb-MRIs for follow-up before progression into MM. Radiological progressive disease (MRI-PD) was defined as detection of new FL or increase in diameter of existing FL and a novel or progressive diffuse infiltration. Radiological stable disease (MRI-SD) was defined by no change compared with the prior MRI. Patients were followed-up every 3-6 months, including a serological and clinical evaluation. One Hundred and eighty-two wb-MRIs were analyzed. MRI-PD occurred in 31 patients (49%), and 25 (40%) patients developed MM. MRI-PD was highly significantly associated with progression into MM, regardless of findings at the initial MRI. In multivariate analysis, MRI-PD remained a risk factor, independent of relevant baseline parameters like serum monoclonal protein or ⩾95% aberrant plasma cells in the bone marrow. Patients with MRI-SD had no higher risk of progression, even when FL were present at the initial MRI. Therefore, MRI is suitable for the follow-up of patients with SMM.
Context. The rotation curve, the total mass and the gravitational potential of the Galaxy are sensitive measurements of the dark matter halo profile. Aims. Cuspy and cored DM halo profiles are ...analysed with respect to recent astronomical constraints in order to constrain the shape of the Galactic DM halo and the local DM density. Methods. All Galactic density components (luminous matter and DM) are parametrized. Then the total density distribution is constrained by astronomical observations: 1) the total mass of the Galaxy, 2) the total matter density at the position of the Sun, 3) the surface density of the visible matter, 4) the surface density of the total matter in the vicinity of the Sun, 5) the rotation speed of the Sun and 6) the shape of the velocity distribution within and above the Galactic disc. The mass model of the Galaxy is mainly constrained by the local matter density (Oort limit), the rotation speed of the Sun and the total mass of the Galaxy from tracer stars in the halo. Results. We showed from a statistical $\chi^2$ fit to all data that the local DM density is strongly positively (negatively) correlated with the scale length of the DM halo (baryonic disc). Since these scale lengths are poorly constrained the local DM density can vary from 0.2 to 0.4 GeV cm-3 ($0.005{-}0.01~M_\odot$ pc-3) for a spherical DM halo profile and allowing total Galaxy masses up to $2 \times 10^{\mathrm{12}}~M_\odot$. For oblate DM haloes and dark matter discs, as predicted in recent N-body simulations, the local DM density can be increased significantly.
Although Corbicula fluminea has been one of the more prolific freshwater invasive species in the world, previous studies have suggested a low probability for overwinter survival in northern latitudes ...without an artificially created thermal refuge. The discovery of live C. fluminea in a central Minnesota lake absent any known thermal refuge in 2020 presented an opportunity to further evaluate the overwinter survival and population structure of C. fluminea at the presumed edge of their potential range. The population was monitored from December 2020 through September 2021 alongside water temperature to better understand at which temperatures C. fluminea survived and if the population structure suggested reproduction occurring in the lake. We documented live C. fluminea in temperatures as low as 0.3°C. Shell size of recovered individuals suggested multiple cohorts, and the appearance of a new cohort at the end of the study, indicating active reproduction in the lake and suggesting the population had likely been present in the lake for at least two winters by the conclusion of the study period. Our findings provide evidence of the survival below historically documented lower lethal temperature limits and suggests adaptations to modeling predicting suitable habitat, both present and in a changing climate, are necessary to better assess risk of invasion by this species.
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