The taccalonolides are highly acetylated steroids that stabilize cellular microtubules and overcome multiple mechanisms of taxane resistance. Recently, two potent taccalonolides, AF and AJ, were ...identified that bind to tubulin directly and enhance microtubule polymerization. Extensive studies were conducted to characterize these new taccalonolides. AF and AJ caused aberrant mitotic spindles and bundling of interphase microtubules that differed from the effects of either paclitaxel or laulimalide. AJ also distinctly affected microtubule polymerization in that it enhanced the rate and extent of polymerization in the absence of any noticeable effect on microtubule nucleation. In addition, the resulting microtubules were found to be profoundly cold stable. These data, along with studies showing synergistic antiproliferative effects between AJ and either paclitaxel or laulimalide, suggest a distinct binding site. Direct binding studies demonstrated that AJ could not be displaced from microtubules by paclitaxel, laulimalide, or denaturing conditions, suggesting irreversible binding of AJ to microtubules. Mass spectrometry confirmed a covalent interaction of AJ with a peptide of β-tubulin containing the cyclostreptin-binding sites. Importantly, AJ imparts strong inter-protofilament stability in a manner different from other microtubule stabilizers that covalently bind to tubulin, consistent with the distinct effects of the taccalonolides as compared with other stabilizers. AF was found to be a potent and effective antitumor agent that caused tumor regression in the MDA-MB-231 breast cancer xenograft model. The antitumor efficacy of some taccalonolides, which stabilize microtubules in a manner different from other microtubule stabilizers, provides the impetus to explore the therapeutic potential of this site.
Time series models relating short-term changes in air pollution levels to daily mortality counts typically assume that the effects of air pollution on the log relative rate of mortality do not vary ...with time. However, these short-term effects might plausibly vary by season. Changes in the sources of air pollution and meteorology can result in changes in characteristics of the air pollution mixture across seasons. The authors developed Bayesian semiparametric hierarchical models for estimating time-varying effects of pollution on mortality in multisite time series studies. The methods were applied to the database of the National Morbidity and Mortality Air Pollution Study, which includes data for 100 US cities, for the period 1987–2000. At the national level, a 10-μg/m3 increase in particulate matter less than 10 μm in aerodynamic diameter at a 1-day lag was associated with 0.15% (95% posterior interval (PI): −0.08, 0.39), 0.14% (95% PI: −0.14, 0.42), 0.36% (95% PI: 0.11, 0.61), and 0.14% (95% PI: −0.06, 0.34) increases in mortality for winter, spring, summer, and fall, respectively. An analysis by geographic region found a strong seasonal pattern in the Northeast (with a peak in summer) and little seasonal variation in the southern regions of the country. These results provide useful information for understanding particle toxicity and guiding future analyses of particle constituent data.
Wastewater from processing crustacean shell features ultrahigh chloride content. Bioremediation of the wastewater is challenging due to the high chloride ion content, making it inhospitable for most ...microorganisms to survive and growth. In this study, mangrove wetland-derived fungi were first tested for their salt tolerance, and the highly tolerant isolates were cultured in shrimp processing wastewater and the chloride concentration was monitored. Notably, the filamentous fungal species
Aspergillus piperis
could remove over 70% of the chloride in the wastewater within 3 days, with the fastest biomass increase (2.01 times heavier) and chloride removal occurring between day one and two. The chloride ions were sequestered into the fungal cells. The genome of this fungal species contained Cl
−
conversion enzymes, which may have contributed to the ion removal. The fungal strain was found to be of low virulence in larval models and could serve as a starting point for further considerations in bioremediation of shell processing wastewater, promoting the development of green technology in the shell processing industry.
The size of the Fontan population with end-stage heart failure is growing. In this population, heart transplantation has been the only option. This study sought to investigate the efficacy of ...ventricular assist device (VAD) support in Fontan patients.
We conducted a retrospective study of Fontan patients in the Advanced Cardiac Therapies Improving Outcomes Network. We evaluated patient characteristics, and the clinical and physiologic outcomes after VAD implantation.
We identified 45 Fontan patients implanted with VAD. The average age of patients was 10 years (interquartile range: 4.5-18) and 30% were female. The majority had a morphologic right ventricle (69%), moderate or greater ventricular dysfunction (83%), and moderate or greater atrioventricular valve regurgitation (65%). The majority of implants were as a bridge to transplantation (76%), and the majority of patients were Interagency Registry for Mechanically Assisted Circulatory Support Profile 2 (56%). The most commonly employed device was the Medtronic HeartWare HVAD (56%). A total of 13 patients were discharged on device support, and 67% of patients experienced adverse events, the most common of which were neurologic (25%). At 1 year after device implantation, the rate of transplantation was 69.5%, 9.2% of patients continued to be VAD supported, and 21.3% of patients had died. Hemodynamically, VAD was effective in decreasing both Fontan and ventricular end-diastolic pressures in some individuals.
VAD is effective in supporting patients with end-stage Fontan failure awaiting heart transplantation. Future research should focus on identifying clinical and physiologic characteristics predictive of a favorable response to VAD support.
Background
Vasculogenic mimicry (VM) is the formation of vascular channels by tumor cells or tumor cell-derived, trans-differentiated cells in highly aggressive, solid tumors. However, the disease ...features and prognostic value of VM for overall survival of cancer patients remain controversial.
Method
To systematically investigate the roles of VM in cancer progression and its prognostic values, we performed a meta-analysis based on 36 studies (33 eligible articles) including 3609 patients. The pooled hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) were used to assess the relationship between VM and overall survival in cancer patients.
Results
Vasculogenic mimicry was significantly associated with cancer differentiation, lymph node metastasis, distant metastasis, and TNM stage. The prognostic value of VM was significant in overall survival (HR 2.16; 95 % CI 1.98–2.38;
P
< 0.001). Analyses stratified by confounders, such as cancer type, ethnicity, VM detection methods, sample size, and Newcastle–Ottawa quality score, found similar significant results.
Conclusions
The presence of VM predicts poorer survival outcomes in cancer patients.
Miscarriage and intrauterine growth restriction (IUGR) are devastating complications in fetal/neonatal alloimmune thrombocytopenia (FNAIT). We previously reported the mechanisms for bleeding ...diatheses, but it is unknown whether placental, decidual immune cells or other abnormalities at the maternal-fetal interface contribute to FNAIT. Here we show that maternal immune responses to fetal platelet antigens cause miscarriage and IUGR that are associated with vascular and immune pathologies in murine FNAIT models. Uterine natural killer (uNK) cell recruitment and survival beyond mid-gestation lead to elevated NKp46 and CD107 expression, perforin release and trophoblast apoptosis. Depletion of NK cells restores normal spiral artery remodeling and placental function, prevents miscarriage, and rescues hemorrhage in neonates. Blockade of NK activation receptors (NKp46, FcɣRIIIa) also rescues pregnancy loss. These findings shed light on uNK antibody-dependent cell-mediated cytotoxicity of invasive trophoblasts as a pathological mechanism in FNAIT, and suggest that anti-NK cell therapies may prevent immune-mediated pregnancy loss and ameliorate FNAIT.Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a gestational disease caused by maternal immune responses against fetal platelets. Using a FNAIT mouse model and human trophoblast cell lines, here the authors show that uterine natural killer cell-mediated trophoblast apoptosis contributes to FNAIT pathogenesis.
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•Chemical ordering annealing on Ni–Mn–Ga microwires was found to reduce the defect density and internal stress.•Chemical ordering annealing on Ni–Mn–Ga microwires was found to ...increase the MT temperatures, Curie point and saturation magnetization.•Chemical ordering annealing on Ni–Mn–Ga microwires was found to decrease the SIM stress and improve the superelastic reversibility.•Chemical ordering annealing on Ni–Mn–Ga microwires was found to weaken the temperature dependences of the superelastic stresses.
Polycrystalline Ni–Mn–Ga microwires of diameter 30–80μm were prepared by melt-extraction technique on a large scale. The rapidly solidified microwires exhibit a fairly high ductility and excellent shape memory property. Here, with the aim to reduce the defect density, internal stress and compositional inhomogeneity in the as-extracted microwires, a stepwise chemical ordering annealing heat treatment was carried out and the effect of annealing on martensitic transformation, magnetic properties and superelastic behavior were investigated. The results indicate that annealing increase the transformation temperature and decrease the transformation hysteresis. These are related to composition homogenization, increase of atomic ordering and decrease in internal stress and defects. During mechanical tests, the stress-induced martensite (SIM) formation took place at a much lower stress after annealing treatment. The annealed microwires also demonstrate a lower superelastic hysteresis and a higher recovery rate compared to the as-extracted microwires. The temperature dependence of SIM stress is weaker after annealing, which is related to the enthalpy change (ΔH) and phase transformation temperature change according to the Clausius–Clapeyron relation.
The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs), supported by The Society of Thoracic Surgeons, provides detailed information on pediatric patients supported with ...ventricular assist devices (VADs).
From September 19, 2012, to December 31, 2021, there were 1355 devices in 1109 patients (<19 years) from 42 North American Hospitals.
Cardiomyopathy was the most common underlying cause (59%), followed by congenital heart disease (25%) and myocarditis (9%). Regarding device type, implantable continuous (IC) VADs were most common at 40%, followed by paracorporeal pulsatile (PP; 28%) and paracorporeal continuous (PC; 26%). Baseline demographics differed, with the PC cohort being younger, smaller, more complex (ie, congenital heart disease), and sicker at implantation (P < .0001). At 6 months after VAD implantation, a favorable outcome (transplantation, recovery, or alive on device) was achieved in 84% of patients, which was greatest among those on IC VADs (92%) and least for PC VADs (69%). Adverse events were not uncommon, with nongastrointestinal bleeding (incidence of 14%) and neurologic dysfunction (11% stroke, 4%), within 2 weeks after implantation being the most prevalent. Stroke and bleeding had negative impacts on overall survival (P = .002 and P < .001, respectively).
This Sixth Pedimacs Report demonstrates the continued evolution of the pediatric field. The complexity of cardiac physiologies and anatomic constraint mandates the need for multiple types of devices used (PC, PP, IC). Detailed analyses of each device type in this report provide valuable information to further advance the care of this challenging and vulnerable population.
A molecular understanding of the regulation of IgG class switching to IL-4-independent isotypes, particularly to IgG2a, remains largely unknown. The T-box transcription factor T-bet directly ...regulates Th1 lineage commitment by CD4 T cells, but its role in B lymphocytes has been largely unexplored. We show here a role for T-bet in the regulation of IgG class switching, especially to IgG2a. T-bet-deficient B lymphocytes demonstrate impaired production of IgG2a, IgG2b, and IgG3 and, most strikingly, are unable to generate germ-line or postswitch IgG2a transcripts in response to IFN-γ. Conversely, enforced expression of T-bet initiates IgG2a switching in cell lines and primary cells. This function contributes critically to the pathogenesis of murine lupus, where the absence of T-bet strikingly reduces B cell-dependent manifestations, including autoantibody production, hypergammaglobulinemia, and immune-complex renal disease and, in particular, abrogates IFN-γ-mediated IgG2a production. Classical T cell manifestations persisted, including lymphadenopathy and cellular infiltrates of skin and liver. These results identify T-bet as a selective transducer of IFN-γ-mediated IgG2a class switching in B cells and emphasize the importance of this regulation in the pathogenesis of humorally mediated autoimmunity.
The rapidly evolving nanotechnology field highlights the need of better understanding the relationship between nanoparticle (NP) properties and NP transport in solid tumors. The present study tested ...the hypothesis that the diffusive transport and spatial distribution of NP can be predicted based on the following parameters: interstitial NP diffusivity, NP–cell interaction parameters (cell surface binding capacity, rate constants of association, dissociation, and internalization). We (a) established the models and equations; (b) experimentally measured, in monolayer pharynx FaDu cells, the model parameters for three NP formulations (negatively charged polystyrene beads, near-neutral liposomes, and positively charged liposomes, with respective diameter of 20, 110, and 130 nm); and (c) used the models and parameters to simulate NP diffusion in 3-dimensional (3D) systems. We next measured the NP concentration–depth profiles in tumor cell spheroids, an avascular 3D system, and found good agreement between model-simulated and experimental data in spheroids for the negative and neutral NP (>90% predicted data points at three NP concentrations and three treatment times were within the 95% confidence intervals of experimental data). Model performance was inferior for positive liposomes containing a fusogenic lipid. The present study demonstrated the possibility of using
in vitro
NP–cell biointerface data in monolayer cultures with
in silico
studies to predict the NP diffusive transport and concentration–time–depth profiles in 3D systems, as functions of NP concentrations and treatment times. Extending this approach to include convective transport may yield a cost-effective means to predict the NP delivery and residence in solid tumors.
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