Low Profiles Research Articles

CSF Protein Level of Neurotransmitter Secretion, Synaptic Plasticity, and Autophagy in PD and DLB

Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis. We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories. (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile. CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Short-Course Antibiotic Prophylaxis Is Associated with Limited Antibiotic Resistance Emergence in Post-Operative Infection of Pelvic Primary Bone Tumor Resection.

Resections of primary pelvic bone tumors are frequently complicated by surgical site infections (SSIs), thereby impairing the functional prognosis of patients, especially in case of implant removal. Although prophylactic antibiotics play an essential role in preventing SSIs, there are presently no recommendations that support their appropriate use. This study aimed to assess the impact of a 24 h prophylactic protocol on the bacterial ecology, the resistance pattern, and the SSI healing rate. We hypothesized that this protocol not only limits the emergence of resistance but also results in a good cure rate with implant retention in case of SSI. A retrospective study was performed that included all patients with an SSI following a pelvic bone tumoral resection between 2005 and 2017 who received a 24 h antibiotic prophylaxis protocol. Twenty-nine patients with an SSI were included. We observed a 75.9% rate of polymicrobial infection, with a high prevalence of digestive flora microorganisms and a majority of wild-type phenotypes. We confirmed that there was no significant emergence of resistant flora. After first-line debridement, antibiotics (DA) if any implant was used, or debridement, antibiotics, and implant retention (DAIR) whenever possible, we obtained a 79.3% cure rate, with implant removal in 20% of cases. The absence of an implant was significantly associated with SSI healing. Early infection management and low resistance profiles may also have a positive effect, but this needs to be confirmed in a larger cohort. In light of this, the use of a 24 h prophylactic protocol in primary pelvic bone tumor resections is associated with a favorable infection cure rate and implant retention in case of SSI, and minimal selection of resistant microorganisms.

Combination of Natural Compounds With Novel Non-thermal Technologies for Poultry Products: A Review.

Ensuring safe, fresh, and healthy food across the shelf life of a commodity is an ongoing challenge, with the driver to minimize chemical additives and their residues in the food processing chain. High-value fresh protein products such as poultry meat are very susceptible to spoilage due to oxidation and bacterial contamination. The combination of non-thermal processing interventions with nature-based alternatives is emerging as a useful tool for potential adoption for safe poultry meat products. Natural compounds are produced by living organisms that are extracted from nature and can be used as antioxidant, antimicrobial, and bioactive agents and are often employed for other existing purposes in food systems. Non-thermal technology interventions such as high-pressure processing, pulsed electric field, ultrasound, irradiation, and cold plasma technology are gaining increasing importance due to the advantages of retaining low temperatures, nutrition profiles, and short treatment times. The non-thermal unit process can act as an initial obstacle promoting the reduction of microflora, while natural compounds can provide an active obstacle either in addition to processing or during storage time to maintain quality and inhibit and control growth of residual contaminants. This review presents the application of natural compounds along with emerging non-thermal technologies to address risks in fresh poultry meat.

Placental morphology and the prediction of underlying cardiovascular risk factors

ObjectivePre-eclampsia is associated with an increased risk of future cardiovascular disease. Maladaptive placentation or malperfusion, as well as predisposing cardiovascular or metabolic risk for endothelial dysfunction, contribute to the systemic inflammatory response that establishes the origins of the disease. The purpose of this study was to investigate the relationship between placental size and cardiovascular risk when assessed at six months postpartum in women who experienced pre-eclampsia. Study DesignMaternal clinical and biochemical cardiovascular risk factors were used to categorize preeclamptic women into high vs. low lifetime cardiovascular disease risk profiles at six months postpartum. A multivariable logistic regression model was then used to identify the association between placental weight to birth weight ratio and high lifetime cardiovascular disease risk, adjusting for maternal age, pre-pregnancy BMI, and severity of pre-eclampsia. A p-value of < 0.05 was deemed statistically significant. Results186/216 women with pre-eclampsia who attended the Maternal Health Clinic met inclusion criteria. No significant differences were observed for placental morphometric measurements between women who screened as having a high vs. low lifetime risk profile for cardiovascular disease at six months postpartum. However, using multivariable modelling that controlled for maternal age, pre-pregnancy body mass index, gestational age at delivery, and severity of pre-eclampsia, a low placenta to birth weight ratio (<15%) was associated with an increased odds of high lifetime cardiovascular disease risk (p < 0.009). ConclusionThe findings of the current study identify clinical measurements that can be collected at the time of delivery which may help identify specific women who may benefit most from postpartum cardiovascular risk screening and intervention.

Metabolomic correlates of coronary atherosclerosis, cardiovascular risk, both or neither. Results of the 2 × 2 phenotypic CAPIRE study

BackgroundTraditional cardiovascular risk factors (RFs) and coronary artery disease (CAD) do not always run parallel. We investigated functional-metabolic correlations of CAD, RFs, or neither in the CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation) 2 × 2 phenotypic observational study. MethodsTwo hundred and fortyone subjects were included based on RF burden, presence/absence of CAD (assessed by computed tomography angiography), age and sex. Participants displayed one of four phenotypes: CAD with ≥3 RFs, no-CAD with ≥3 RFs, CAD with ≤1 RF and no-CAD with ≤1 RF. Metabolites were identified by gas chromatography–mass spectrometry and pathways by metabolite set enrichment analysis. ResultsCharacteristic patterns and specific pathways emerged for each phenotypic group: amino sugars for CAD/high-RF; urea cycle for no-CAD/high-RF; glutathione for CAD/low-RF; glycine and serine for no-CAD/low-RF. Presence of CAD correlated with ammonia recycling; absence of CAD with the transfer of acetyl groups into mitochondria; high-risk profile with alanine metabolism (all p < 0.05).The comparative case-control analyses showed a statistically significant difference for the two pathways of phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism in the CAD/Low-RF vs NoCAD/Low-RF comparison. ConclusionsThe present 2 × 2 observational study identified specific metabolic pathways for each of the four phenotypes, providing novel functional insights, particularly on CAD with low RF profiles and on the absence of CAD despite high-risk factor profiles.

HER2 in uterine serous carcinoma: Testing platforms and implications for targeted therapy.

5580 Background: HER2 is an emerging prognostic and therapeutic target in uterine serous carcinoma (USC). Testing algorithms and platforms in breast and gastric cancers are well studied and validated, but optimal HER2 testing in uterine cancer is not yet established. We aimed to assess the concordance of chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) platforms to aid in the development of USC specific testing guidelines. We also evaluated the rate of downstream mutations that may affect response to HER2 directed therapy. Methods: A total of 2,192 USC tumors were analyzed using NGS (NextSeq, 592 Genes and WES, NovaSEQ), a subset of 1,423 tumors were also tested by IHC and CISH (Caris Life Sciences, Phoenix, AZ). HER2 positivity through IHC (4B5, Ventana) and CISH (INFORM DUAL HER2 ISH Assay, Ventana) was determined based on 2007 and 2018 ASCO/CAP HER2 breast cancer guidelines. PD-L1 expression was tested by IHC using SP142 (Spring Biosciences) (positive cut-off &gt;1%). Microsatellite instability (MSI) was tested by fragment analysis (FA), IHC and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cut-off &gt; 10 mutations per Mb). Statistical significance was determined using chi-square. Results: Rates of HER2 positivity were comparable using the 2018 and 2007 breast cancer guidelines (19.5% vs 17.5%; p=0.25). Based on 2018 guidelines, the concordance between IHC and CISH was 98.9%. Specifically, 229/1423 patients (16%) were IHC+/CISH+, 5 patients (0.4%) were IHC+/CISH- and 11 patients (0.8%) were IHC-/CISH+ (Table). Common pathway alterations in HER2+ USC include TP53, RTK RAS, PI3K, NOTCH, chromatin remodeling and cell cycle genes. Single gene alterations in HER2+ tumors that may implicate HER2 therapy resistance (based on pathway analyses in other tumor types) included PI3K (36%), KRAS (2.6%), and PTEN (2.1%). HER2+ tumors had low immunotherapy biomarker profiles (0.3% MSI-H, 0.8% TMB, 17.1% PD-L1). Conclusions: High concordance rates were observed between CISH and IHC. Ultimately these testing platforms need to be validated by response to HER2 targeted therapies in order to develop USC specific HER2 testing guidelines.[Table: see text]

Error propagation dynamics of velocimetry-based pressure field calculations (2): on the error profile

A recent study investigated the propagation of error in a velocimetry-based pressure (V-pressure) field reconstruction problem by directly analyzing the properties of the pressure Poisson equation (Pan et al 2016 Meas. Sci. Technol. 27 084012). In the present work, we extend these results by quantifying the effect of the error profile in the data field (shape/structure of the error in space) on the resultant error in the reconstructed pressure field. We first calculate the mode of the error in the data that maximizes error in the pressure field, which is the most dangerous error (called the worst error in the present work). This calculation of the worst error is equivalent to finding the principle mode of, for example, an Euler–Bernoulli beam problem in one-dimension and the Kirchhoff–Love plate in two-dimensions, thus connecting the V-pressure problem from experimental fluid mechanics to buckling elastic bodies from elastic mechanics. Taking advantage of this analogy, we then analyze how the error profile (e.g. spatial frequency of the error and the location of the most concentrated error) in the data field coupled with fundamental features of the flow domain (i.e. size, shape, and dimension of the domain, and the configuration of boundary conditions) significantly affects the error propagation from data to the reconstructed pressure. Our analytical results lend to practical applications in two ways. First, minimization of error propagation can be achieved by avoiding low frequency error profiles in data similar to the worst case scenarios and error concentrated at sensitive locations. Second, small amounts of the error in the data, if the error profile is similar to the worst error case, can cause significant error in the reconstructed pressure field; such a synthetic error can be used to benchmark V-pressure algorithms.

Vectored Immunotherapeutics for Infectious Diseases: Can rAAVs Be The Game Changers for Fighting Transmissible Pathogens?

Conventional vaccinations and immunotherapies have encountered major roadblocks in preventing infectious diseases like HIV, influenza, and malaria. These challenges are due to the high genomic variation and immunomodulatory mechanisms inherent to these diseases. Passive transfer of broadly neutralizing antibodies may offer partial protection, but these treatments require repeated dosing. Some recombinant viral vectors, such as those based on lentiviruses and adeno-associated viruses (AAVs), can confer long-term transgene expression in the host after a single dose. Particularly, recombinant (r)AAVs have emerged as favorable vectors, given their high in vivo transduction efficiency, proven clinical efficacy, and low immunogenicity profiles. Hence, rAAVs are being explored to deliver recombinant antibodies to confer immunity against infections or to diminish the severity of disease. When used as a vaccination vector for the delivery of antigens, rAAVs enable de novo synthesis of foreign proteins with the conformation and topology that resemble those of natural pathogens. However, technical hurdles like pre-existing immunity to the rAAV capsid and production of anti-drug antibodies can reduce the efficacy of rAAV-vectored immunotherapies. This review summarizes rAAV-based prophylactic and therapeutic strategies developed against infectious diseases that are currently being tested in pre-clinical and clinical studies. Technical challenges and potential solutions will also be discussed.

Detecting Attention Levels in ADHD Children with a Video Game and the Measurement of Brain Activity with a Single-Channel BCI Headset.

Attentional biomarkers in attention deficit hyperactivity disorder are difficult to detect using only behavioural testing. We explored whether attention measured by a low-cost EEG system might be helpful to detect a possible disorder at its earliest stages. The GokEvolution application was designed to train attention and to provide a measure to identify attentional problems in children early on. Attention changes registered with NeuroSky MindWave in combination with the CARAS-R psychological test were used to characterise the attentional profiles of 52 non-ADHD and 23 ADHD children aged 7 to 12 years old. The analyses revealed that the GokEvolution was valuable in measuring attention through its use of EEG–BCI technology. The ADHD group showed lower levels of attention and more variability in brain attentional responses when compared to the control group. The application was able to map the low attention profiles of the ADHD group when compared to the control group and could distinguish between participants who completed the task and those who did not. Therefore, this system could potentially be used in clinical settings as a screening tool for early detection of attentional traits in order to prevent their development.

Identifying and predicting food parenting practice profiles among Canadian parents

BackgroundFood parenting practices (FPP) can affect children’s eating behaviours, yet little is known about how various FPP co-occur. The primary aim was to identify profiles of FPPs use among Canadian parents. Secondary aims included examining sociodemographic correlates of FPP profiles and evaluating whether children’s eating behaviours differed across FPP profiles.MethodsParents (n = 799) of 5–12-year-old children completed a validated FPP Item Bank and the Children’s Eating Behaviour Questionnaire. Latent Class Analysis (LCA) was used to identify distinct FPP profiles. Regression analyses were used to explore associations between FPP profiles, sociodemographic variables (race, sex and education) and children’s eating behaviours (emotional overeating, food responsiveness, food fussiness and satiety responsiveness).ResultsLCA revealed 6 FPP profiles: healthy eating environment, high engagement, reactive, high structure, controlling and low engagement. Relative to their non-White counterparts, White parents were more likely to belong in the healthy eating environment, high structure and low engagement profiles. Relative to fathers, mothers were more likely to fall in the healthy eating environment compared to low engagement profile. Parents with some post-secondary education were more likely to belong in the healthy eating environment, high structure and reactive profiles compared to the controlling profile. Emotional overeating and food responsiveness scores were lowest for healthy eating environment, high structure, low engagement profiles. Parents in the healthy eating environment profile also reported lower food fussiness scores compared to parents in the high engagement, high structure, reactive and controlling profiles.ConclusionsFindings suggest that a continuum of 6 FPP profiles may be present among Canadian parents, representing parents who use either all (high engagement), some (healthy eating environment, reactive, high structure, controlling) or little (low engagement) of the FPP examined. Future longitudinal research should evaluate how various FPP profiles influence the development of children’s eating behaviors, dietary intakes and weight status.

Characterization of Cold-Tolerant Saccharomyces cerevisiae Cheongdo Using Phenotype Microarray.

The cold-tolerant yeast Saccharomyces cerevisiae is industrially useful for lager fermentation, high-quality wine, and frozen dough production. S. cerevisiae Cheongdo is a recent isolate from frozen peach samples which has a good fermentation performance at low temperatures and desirable flavor profiles. Here, phenotype microarray was used to investigate industrial potentials of S. cerevisiae Cheongdo using 192 carbon sources. Compared to commercial wine yeast S. cerevisiae EC1118, Cheongdo showed significantly different growth rates on 34 substrates. The principal component analysis of the results highlighted that the better growth of Cheongdo on galactose than on EC1118 was the most significant difference between the two strains. The intact GAL4 gene and the galactose fermentation performance at a low temperatures suggested that S. cerevisiae Cheongdo is a promising host for industrial fermentation rich in galactose, such as lactose and agarose.

Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience

Background/aim Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization. Materials and methods Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60. Results On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care. Conclusion We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides.

Lipid nanoparticles (LNPs) constitute a facile and scalable approach for delivery of payloads to human cells. LNPs are relatively immunologically inert and can be produced in a cost effective and scalable manner. However, targeting and delivery of LNPs across the blood–brain barrier (BBB) has proven challenging. In an effort to target LNPs composed of an ionizable cationic lipid (DLin-MC3-DMA), cholesterol, the phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000) to particular cell types, as well as to generate LNPs that can cross the BBB, we developed and assessed two approaches. The first was centered on the BBB-penetrating trans-activator of transcription (Tat) peptide or the peptide T7, and the other on RNA aptamers targeted to glycoprotein gp160 from human immunodeficiency virus (HIV) or C-C chemokine receptor type 5 (CCR5), a HIV-1 coreceptor. We report herein a CCR5-selective RNA aptamer that acts to facilitate entry through a simplified BBB model and that drives the uptake of LNPs into CCR5-expressing cells, while the gp160 aptamer did not. We further observed that the addition of cell-penetrating peptides, Tat and T7, did not increase BBB penetration above the aptamer-loaded LNPs alone. Moreover, we found that these targeted LNPs exhibit low immunogenic and low toxic profiles and that targeted LNPs can traverse the BBB to potentially deliver drugs into the target tissue. This approach highlights the usefulness of aptamer-loaded LNPs to increase target cell specificity and potentially deliverability of central-nervous-system-active RNAi therapeutics across the BBB.

Cholinium-based ionic liquids as bioinspired hydrotropes to tackle solubility challenges in drug formulation

Hydrotropy is a well-established strategy to enhance the aqueous solubility of hydrophobic drugs, facilitating their formulation for oral and dermal delivery. However, most hydrotropes studied so far possess toxicity issues and are inefficient, with large amounts being needed to achieve significant solubility increases. Inspired by recent developments in the understanding of the mechanism of hydrotropy that reveal ionic liquids as powerful hydrotropes, in the present work the use of cholinium vanillate, cholinium gallate, and cholinium salicylate to enhance the aqueous solubility of two model drugs, ibuprofen and naproxen, is investigated.It is shown that cholinium vanillate and cholinium gallate are able to increase the solubility of ibuprofen up to 500-fold, while all three ionic liquids revealed solubility enhancements up to 600-fold in the case of naproxen. Remarkably, cholinium salicylate increases the solubility of ibuprofen up to 6000-fold. The results obtained reveal the exceptional hydrotropic ability of cholinium-based ionic liquids to increase the solubility of hydrophobic drugs, even at diluted concentrations (below 1 mol·kg−1), when compared with conventional hydrotropes. These results are especially relevant in the field of drug formulation due to the bio-based nature of these ionic liquids and their low toxicity profiles. Finally, the solubility mechanism in these novel hydrotropes is shown to depend on synergism between both amphiphilic ions.

Number of siblings and survival from childhood leukaemia: a national register-based cohort study from Sweden.

Previous studies suggest worse leukaemia survival for children with siblings, but the evidence is sparse, inconsistent and does not consider clinical factors. We explored the associations between number of siblings in the household, birth order and survival from childhood acute lymphoid leukaemia (ALL) and acute myeloid leukaemia (AML). In this nationwide register-based study we included all children aged 1-14, diagnosed with ALL and AML between 1991-mid-2015 in Sweden (n = 1692). Using Cox regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) according to number of siblings and birth order, adjusting for known prognostic and sociodemographic factors. A tendency towards better ALL survival among children with one, or ≥2, siblings was observed, adjHRs (95% CI): 0.73 (0.49-1.10) and 0.63 (0.40-1.00), respectively. However, this was mainly limited to children with low risk profiles. An indication of better AML survival among children with siblings was seen, adjHRs (95% CI) 0.68 (0.36-1.29) and 0.71 (0.34-1.48) but diminished after adjusting for birth order. Our results do not support previous findings that a larger number of siblings is associated with poorer survival. Inconsistencies might be explained by underlying mechanisms that differ between settings, but chance cannot be ruled out.

Chemical Glycosylation and Its Application to Glucose Homeostasis-Regulating Peptides.

Peptides and proteins are attractive targets for therapeutic drug development due to their exquisite target specificity and low toxicity profiles. However, their complex structures give rise to several challenges including solubility, stability, aggregation, low bioavailability, and poor pharmacokinetics. Numerous chemical strategies to address these have been developed including the introduction of several natural and non-natural modifications such as glycosylation, lipidation, cyclization and PEGylation. Glycosylation is considered to be one of the most useful modifications as it is known to contribute to increasing the stability, to improve solubility, and increase the circulating half-lifves of these biomolecules. However, cellular glycosylation is a highly complex process that generally results in heterogenous glycan structures which confounds quality control and chemical and biological assays. For this reason, much effort has been expended on the development of chemical methods, including by solid phase peptide synthesis or chemoenzymatic processes, to enable the acquisition of homogenous glycopeptides to greatly expand possibilities in drug development. In this mini-review, we highlight the importance of such chemical glycosylation methods for improving the biophysical properties of naturally non-glycosylated peptides as applied to the therapeutically essential insulin and related peptides that are used in the treatment of diabetes.

Self‐Assembly of Cholesterol‐Doxorubicin and TPGS into Prodrug‐Based Nanoparticles with Enhanced Cellular Uptake and Lysosome‐Dependent Pathway in Breast Cancer Cells

AbstractDeveloping new easy‐to‐prepare functional drug delivery nanosystems with good storage stability, low hemotoxicity, as well as controllable drug delivery property, has attracted great attention in recent years. In this work, a cholesterol‐based prodrug nanodelivery system is prepared by self‐assembly of cholesterol‐doxorubicin prodrug conjugates (Chol‐Dox) and tocopherol polyethylene glycol succinate (TPGS) using thin‐film hydration method. The Chol‐Dox/TPGS assemblies (molar ratio 2:1, 1:1, and 1:2) are able to form nanoparticles with average hydrodynamic diameter of ≈140–214 nm, surface zeta potentials of ≈−24.2–−0.3 mV, and remarkable solution stability in 0.1 m PBS, 16 days). The Chol‐Dox/TPGS assemblies show low hemotoxicity and different cytotoxicity profiles in breast cancer cells (MCF‐7 and MDA‐MB‐231), which are largely dependent on the molar ratio of Chol‐Dox and TPGS. The Chol‐Dox/TPGS assemblies tend to enter into MCF‐7 and MDA‐MB‐231 cells through non‐Clathrin‐mediated multiple endocytosis and lysosome‐dependent uptake pathways, moreover, these nanoassemblies demonstrate lysosome‐dependent intracellular localization, which is different from that of free DOX (nuclear localization). The results demonstrate that the Chol‐Dox/TPGS assemblies are promising cholesterol‐based prodrug nanomaterials for breast cancer chemotherapy.Practical Applications: This work demonstrates a lipid prodrug‐based nanotherapeutic system. Herein the Chol‐Dox/TPGS nanoassemblies could serve as promising and controllable cholesterol‐based prodrug nanomaterials/nano‐formulations for potential breast cancer chemotherapy.

Missouri Experimental Sonic Arts Festival (MOXsonic)

Missouri Experimental Sonic Arts Festival (MOXsonic)

Ultrasound-guided transrectal implantation of fiducial markers for image-guided radiotherapy of prostate cancer without local anesthesia: Patient-reported gastrointestinal-genitourinary system complications and pain.

The present study evaluates procedure-associated pain and side effects in the gastrointestinal-genitourinary system in patients with early-stage prostate cancer who were treated with image-guided radiotherapy (IGRT), accompanied by an ultrasound-guided transrectal implantation of fiducial markers, without local anesthesia. A total of 46 patients who referred to our clinics between 2012 and 2017 with a diagnosis of early-stage prostate cancer were included in the study. Before undergoing radiotherapy, all patients were implanted with three intraprostatic fiducial markers through the ultrasound-guided transrectal approach without local anesthesia. The patients underwent radiotherapy after the clinical target volumes were established, in accordance with the respective risk groups, and localization of the markers was confirmed before each therapy session. The levels of procedure-associated pain and side effects were graded immediately after the procedure through the use of a patient-based scoring system. The faces pain scale - revised version was used for the measurement of the severity of procedure-associated pain. Of the total study sample, the facial expressions of 38 patients (35%) corresponded to level 0 in the study, seven (15%) to level 2, and a single patient (2%) to level 4. None of the facial expressions of the patients corresponded to levels 6, 8, or 10. The evaluation of procedure-related genitourinary and gastrointestinal system side effects indicated that nine patients (20%) experienced side effects, while no side effects were reported in 37 patients (80%). The reported side effects included rectal bleeding in two patients (4%), dysuria in three patients (6%), hematuria in five patients (11%), and frequent urination in five patients (11%). None of the patients experienced fever or hematospermia. All side effects were reported by the respondents as "a little," while only one patient answered positively to the question on the frequency of urination. Among the patients who answered "yes" and "a little" to the questions evaluating genitourinary and gastrointestinal system side effects, the severity of these events was reported as Grade 1, corresponding to mild adverse, in only 9 (20%) patients. None of the patients experienced a Grade 2 or higher severe adverse event. In the comparison of the severity of pain of the patients during the fiducial marker procedure without local anesthesia with the severity of pain during the biopsy, 24 patients (80%) reported "lower" levels of pain, while five patients (20%) reported "equal" levels of pain. None of the patients stated that they had experienced "more" pain. IGRT accompanied by an ultrasound-guided implantation of fiducial markers without local anesthesia can be considered a safe method, given the associated acceptable levels of pain, low side effect profiles, and high prostate-specific antigen control rates.

Design, synthesis and biological activity of N-(amino)piperazine-containing benzothiazinones against Mycobacterium tuberculosis.

A series of novel benzothiazinone derivatives containing a N-(amino)piperazine moiety, based on the structure of WAP-1902 discovered in our lab, were designed and synthesized as new anti-TB agents. Many of the compounds exhibited excellent invitro activity against both drug-sensitive MTB strain H37Rv and multidrug-resistant clinical isolates (MIC: < 0.016μg/mL), and good safety index (CC50: >64μg/mL). Especially compound 1o displayed low hERG cardiac toxicity and acceptable oral pharmacokinetic profiles, indicating its promising potential to be a lead compound for future antitubercular drug discovery.