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Background: This study aimed to examine the effectiveness and safety of eribulin used as an early-line (EL, i.e., first-/second-line) versus late-line (LL, i.e., third-line and beyond) chemotherapy for recurrent advanced or metastatic breast cancer (A/MBC) patients. Methods: This study conducted a retrospective observation of A/MBC patients initiating eribulin between January 1, 2015, and June 30, 2019, using medical database at a university-affiliated teaching hospital in Taiwan. Patients were assigned into either the EL or LL group based on the timing of respective eribulin treatments and were observed for at least 6 months up to December 2019 for progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), disease response, and occurrence of adverse events. The Kaplan-Meier and Cox proportional hazard regression survival analyses were performed. Results: Of 127 patients, 23.6% (n = 30) and 76.4% (n = 97) were assigned to the EL and LL groups, respectively, between which no difference in patient characteristics was noted. Median PFS and TTF were 6.5 months and 5.0 months for the EL and 4.2 months and 3.4 months for the LL, respectively. Median OS could not be estimated in the EL group and was 20.5 months in the LL group. Eribulin as an EL treatment was the only factor associated with longer TTF and OS, whereas the number of metastatic sites was additionally associated with PFS in the multivariate analysis. No complete response was reported in either group, but a partial response was obtained in 6.7% in the EL group and 3.1% in the LL group. The common adverse events between two groups were similar, including leukopenia (80.0%), neutropenia (76.7%), and anemia (60.0%). Conclusions: The eribulin used as an EL of chemotherapy was effective for A/MBC patients with known toxicities in this study, while eribulin as the LL chemotherapy showed consistent results with previous reports.

Salting is an essential step in the production of Cheddar and other cheese varieties and is a well-studied process but the effect of salt addition on the microstructure of the milk ingredients and resulting cheese is not well known. This study provides insights into how the primary components in milk and the cheese matrix respond to salting. High concentrations of salt (15–25% (w/w) NaCl) disrupted fat globules due to the increased osmotic pressure. This led to fat coalescence, resulting in large fat globules >10 μm in diameter, together with submicron sized fat globules ~ 120–500 nm in diameter. Salt addition also prevented the visualization of the milk fat globule membrane when added at high concentrations (25% (w/w) NaCl) and induced asymmetry in liquid ordered domains at lower concentrations (10% (w/w) NaCl). The microstructure of the surface of the milled curd was compacted by salt, appearing coarse with 5% (w/w) NaCl or more hydrated with a denser protein structure with 2.5% (w/w) NaCl. After pressing, the curd junctions were fine and thin within the unsalted sample but coarse and thick where 5% (w/w) NaCl was added. Such coarse junctions appear to reduce binding between curd particles leading to a less cohesive cheese. Our results show that NaCl can significantly impact on the structure of fat and protein matrix of the curd surface if salt is not evenly distributed during dry salting. High concentrations of salt can also change the microstructure and texture of the cheese, resulting in a more heterogeneous product.

International audience; A disintegrin and metalloprotease 10 (ADAM10) is a transmembrane protein essential for embryonic development, and its dysregulation underlies disorders such as cancer, Alzheimer's disease, and inflammation. ADAM10 is a “molecular scissor” that proteolytically cleaves the extracellular region from >100 substrates, including Notch, amyloid precursor protein, cadherins, growth factors, and chemokines. ADAM10 has been recently proposed to function as six distinct scissors with different substrates, depending on its association with one of six regulatory tetraspanins, termed TspanC8s. However, it remains unclear to what degree ADAM10 function critically depends on a TspanC8 partner, and a lack of monoclonal antibodies specific for most TspanC8s has hindered investigation of this question. To address this knowledge gap, here we designed an immunogen to generate the first monoclonal antibodies targeting Tspan15, a model TspanC8. The immunogen was created in an ADAM10-knockout mouse cell line stably overexpressing human Tspan15, because we hypothesized that expression in this cell line would expose epitopes that are normally blocked by ADAM10. Following immunization of mice, this immunogen strategy generated four Tspan15 antibodies. Using these antibodies, we show that endogenous Tspan15 and ADAM10 co-localize on the cell surface, that ADAM10 is the principal Tspan15-interacting protein, that endogenous Tspan15 expression requires ADAM10 in cell lines and primary cells, and that a synthetic ADAM10/Tspan15 fusion protein is a functional scissor. Furthermore, two of the four antibodies impaired ADAM10/Tspan15 activity. These findings suggest that Tspan15 directly interacts with ADAM10 in a functional scissor complex.

β-casein (β-CN) comprises a major portion of milk caseins and are present as several genetic variants. In this study, we investigated the effects of the β-CN A2 variant versus the A1 variant on the calcium distribution, acid gelation and foaming properties of milk, and the microstructure of acid milk gels. The results showed that milk containing the β-CN phenotype A2A2 had a higher proportion of free ionic calcium, enhanced foam formation capability and required a longer time for gelation to occur. The storage modulus at the end of fermentation was significantly lower for β-CN A2A2 milk gel compared with that from β-CN A1A1 milk. The microstructures of the gels characterised by both confocal microscopy and Cryo-SEM demonstrated the differences in the gel porosity and protein strand thickness. The more porous microstructure and thinner protein strands in the β-CN A2A2 milk gel resulted in a lower gel strength compared to β-CN A1A1 milk gel. These findings provide new insights to the subtle differences in the physical properties of milk containing β-CN A2A2 and A1A1 phenotypes, which could support dairy producers in the development of new dairy products with different functional properties.

Fermentation of milk is commonly used throughout the world to produce a variety of foods with different health benefits. We hypothesised that due to differences in physicochemical properties and protein sequences among milk from different species and their fermented yogurt samples, their protein digestion and resulting peptide profiles would differ. Cow, goat and sheep milk and yogurt were compared at designated timepoints throughout in vitro gastric and intestinal digestion for differences in peptide profiles and peptide bioactivities. The results showed that most proteins in all milk and yogurt samples were digested within the early phase of gastric digestion. β-Lg and β-CN were digested faster in yogurt than milk, which was most evident for sheep products. Regardless of species, in vitro gastric and intestinal digestion released a higher concentration of specific peptides, particularly anti-hypertensives, from yogurt compared with their milk counterparts.

Milk processing affects the molecular and supramolecular characteristics of milk. While many of these changes have been studied extensively, the effect of homogenisation on volatile components and lipids at different pressures and temperatures is still poorly understood. The aim of this study was to determine the effect of homogenisation pressure (0, 150, 250 and 350 bar) at different temperatures (45 °C, 60 °C and 80 °C) on the content of individual milk volatile components, phospholipids and triacylglycerols. The results demonstrated the importance of temperature and pressure (P > 0.001) on the formation of 2-heptanone. Temperature was the most important factor for significant (P > 0.05) loss of the milk fat globule membrane lipid phosphatidyletholamine (PE) from the milk serum. Moreover, a significant increase (P > 0.001) in the level of all triacylglycerols groups in the serum phase of homogenised milk was observed, independent of the temperature of the homogenisation process.

This study employed a semi-quantitative, multiplexed tandem PCR (MT-PCR) to assess the prevalence and infection intensity of four genotypes (buffeli, chitose, ikeda and type 5) of Theileria orientalis in cattle in Australia. Genomic DNA samples from blood samples (n=448) collected from 27 to 32 dairy cows from each of 15 dairy herds with a history of recent theileriosis outbreaks (Group 1), and from blood samples available from 24 cows with or without oriental theileriosis (Group 2) were tested using MT-PCR. Results revealed that all four genotypes were present in Group 1 cattle; genotype buffeli had the highest prevalence (80.5%), followed by genotypes ikeda (71.4%), chitose (38.6%) and type 5 (20.3%). Genotype ikeda had the highest average infection intensity in the cattle (relating to 55,277 DNA copies), followed by buffeli, chitose and type 5 (6354-51,648 copies). For Group 2, results indicated that genotype ikeda had a significantly higher average intensity of infection than buffeli in symptomatic cattle (P

Mozzarella cheese is a classical dairy product but most research to date has focused on low moisture products. In this study, the microstructure and physicochemical properties of both laboratory and commercially produced high moisture buffalo Mozzarella cheeses were investigated and compared to high moisture bovine products. Buffalo and bovine Mozzarella cheeses were found to significantly differ in their microstructure, chemical composition, organic acid and proteolytic profiles but had similar hardness and meltability. The buffalo cheeses exhibited a significantly higher ratio of fat to protein and a microstructure containing larger fat patches and a less dense protein network. Liquid chromatography mass spectrometry detected the presence of only β-casein variant A2 and a single β-lactoglobulin variant in buffalo products compared to the presence of both β-casein variants A1 and A2 and β-lactoglobulin variants A and B in bovine cheese. These differences arise from the different milk composition and processing conditions. The differences in microstructure and physicochemical properties observed here offer a new approach to identify the sources of milk used in commercial cheese products.

A new species of strongyloid nematode from the genus Cloacina (Chabertiidae: Cloacininae) is described from the stomach of the hill kangaroo or euro (Macropus robustus) (Marsupialia: Macropodidae) from Western Australia. Cloacina atthis sp. nov. was found only in euros from the Pilbara region in the northwest of Western Australia, in spite of extensive collecting of the same host species from around the Australian continent. C. atthis is most closely related to Cloacina clymene, a species found in the same host species but only in the eastern half of the continent; the two species differ in minor morphological features (the shape of the wall of the buccal capsule, spicule lengths, the degree of sclerotisation of the gubernaculum and the shape of the vagina) as well as in differences in the internal transcribed spacers of ribosomal DNA. This study highlights the importance of using molecular methods when investigating the apparently disjunct distributions of strongyloid nematodes.

The production of whey protein concentrate powders is often limited by the fouling of the ultrafiltration membranes and the low heat stability of the whey protein solutions. Ultrasonic treatment of whey solutions has previously been shown to break down protein aggregates and improve heat stability. This study investigates the use of ultrasound as a pre-treatment step to improve downstream ultrafiltration performance. Results show that sonication alone alleviated membrane fouling to a small extent. However, the use of ultrasound following heat exposure reduced membrane pore blockage and growth of the foulant cake greatly, relative to heat exposure in the absence of ultrasound. The extent of changes to pore blockage and cake growth was greater at higher solids concentration. In all cases, the protein concentration in the permeate remained unchanged. This work has the potential to reduce energy requirements in the ultrafiltration of whey as feed pre-treatment by both ultrasound and the combination of heat and ultrasound produced a lower viscosity feed solution.

The properties of buffalo and bovine milk differ and the procedures developed to make bovine yoghurt may require optimisation for the production of buffalo yoghurt. This study aimed to apply cryo-scanning electron microscopy and confocal laser scanning microscopy to determine the optimal temperature for processing buffalo yoghurt. Milk was fermented at three different temperatures (37, 40 and 43 °C), stored for 28 days and the yoghurt microstructure, physicochemical and rheological properties assessed. Yoghurt fermented at 37 °C had a compact microstructure and the probiotic Lactobacillus acidophilus La-5 was more viable on storage. In contrast, yoghurt produced from a faster fermentation at 43 °C was firmer with a more porous microstructure that exhibited a higher degree of syneresis. The rheological properties during storage including the thixotropy, consistency coefficient and flow behaviour index were not significantly affected by temperature nor were the concentration of lactose, ionic calcium or titratable acidity. This study shows how changes to processing can be used to alter the microstructure of buffalo products and suggests that a decrease in fermentation temperature could be used to improve the quality of buffalo yoghurt.

The physicochemical and rheological properties of yoghurt made from unstandardised unhomogenised buffalo milk were investigated during fermentation and 28 days of storage and compared to the properties of yoghurt made from homogenised fortified bovine milk. A number of differences observed in the gel network can be linked to differences in milk composition. The microstructure of buffalo yoghurt, as assessed by confocal laser scanning microscopy (CLSM) and cryo scanning electron microscopy (cryo-SEM), was interrupted by large fat globules and featured more serum pores. These fat globules have a lower surface area and bind less protein than the homogenised fat globules in bovine milk. These microstructural differences likely lead to the higher syneresis observed for buffalo yoghurt with an increase from 17.4 % (w/w) to 19.7 % (w/w) in the weight of whey generated at days 1 and 28 of the storage. The higher concentration of total calcium in buffalo milk resulted in the release of more ionic calcium during fermentation. Gelation was also slower but the strength of the two gels was similar due to similar protein and total solids concentrations. Buffalo yoghurt was more viscous, less able to recover from deformation and less Newtonian than bovine yoghurt with a thixotropy of 3,035 Pa.s−1 measured for buffalo yoghurt at the end of the storage, at least four times higher than the thixotropy of bovine yoghurt. While the titratable acidity, lactose consumption and changes in organic acid concentrations were similar, differences were recorded in the viability of probiotic bacteria with a lower viability of Lactobacillus acidophilus of 5.17 log (CFU/g) recorded for buffalo yoghurt at day 28 of the storage. Our results show that factors other than the total solids content and protein concentration of milk affect the structural properties of yoghurt. They also illustrate the physicochemical reasons why buffalo and bovine yoghurt are reported to have different sensory properties and provide insight into how compositional changes can be used to alter the microstructure and properties of dairy products.

Understanding the mechanisms that generate oscillations in the incidence of childhood infectious diseases has preoccupied epidemiologists and population ecologists for nearly two centuries. This body of work has generated simple yet powerful explanations for the epidemics of measles and chickenpox, while the dynamics of other infectious diseases, such as whooping cough, have proved more challenging to decipher. A number of authors have, in recent years, proposed that the noisy and somewhat irregular epidemics of whooping cough may arise due to stochasticity and its interaction with nonlinearity in transmission and seasonal variation in contact rates. The reason underlying the susceptibility of whooping cough dynamics to noise and the precise nature of its transient dynamics remain poorly understood. Here we use household data on the incubation period in order to parametrize more realistic distributions of the latent and infectious periods. We demonstrate that previously reported phenomena result from transients following the interaction between the stable annual attractor and unstable multiennial solutions.

Milk fat globules and their surrounding biological membrane (the MFGM) are not well understood despite the importance of these milk components in human nutrition and the role of fat globules in determining the properties of dairy products. The objectives of this study were to investigate these unique colloidal assemblies and the microstructure of the MFGM in buffalo milk, which is the second largest global source of dairy products. In-situ structural investigations were performed at room temperature using confocal microscopy with multiple fluorescent probes (Nile Red, Rh-DOPE, the lectin WGA-488). Microscopic observations showed cytoplasmic crescents around fat globules and the heterogeneous distribution of glycosylated molecules and polar lipids with the occurrence of lipid domains. The lipid domains in the buffalo MFGM appear to form by the segregation of lipids with a high phase transition temperature (e.g. sphingomyelin and saturated phosphatidylcholine molecular species) and cholesterol resulting in a gel phase or a Lo phase forming circular domains. The structure of the buffalo MFGM results from a non-random mixing of components, consistent with observations for other species. Structural heterogeneities of the MFGM could affect the processability of buffalo fat globules and the bioavailability of milk lipids.

CRP is named such for its ability to precipitate the somatic C-polysaccharide of Streptococcus pneumoniae. This polypeptide acute phase reactant is a sensitive systemic marker of inflammation, malignancy and tissue damage. ABX Diagnostics developed a hematology analyzer (Micros CRP), which rapidly measures 16 routine hematological parameters plus whole blood CRP. The CRP value, determined by specific antigen-antibody induced optical turbidity, is available within 5 minutes with sensitivity to 0.10 mg/dl. Normal whole blood values range between 0.0 to 0.2 mg/dl. We evaluated the added clinical benefit of immediate CRP determinations in an outpatient cancer clinic in 155 patients undergoing observation and aggressive chemotherapy. Blood was obtained from all patients each visit and routine CBC, Platelet count and CRP were recorded, immediately provided to the physician in the presence of the patient and automatically stored in a database (HemaLink). Correlations were made between changes of CRP, WBC, AGC, and clinical condition. Routine measurement of CRP and its immediate availability for clinical interpretation was found to add a valuable new diagnostic dynamic for cancer patient care. Elevated CRP and its relative change were found to be a leading indicator of serious and frequently subclinical infection and were the earliest clues when compared to WBC or AGC. Relative changes of CRP were found to be indicative of clinical course. Diagnostic value of the WBC in cancer patients was lost in those undergoing myelosuppressive therapy and in those receiving leukocyte colony stimulating factors. The immediate availability of CRP allowed for preemptive diagnostics and therapy. Real-time knowledge of CRP either changed or significantly influenced therapy in 38% of patients. Study supported in part by ThinkTwice Technologies.

We measured serum folic acid, total serum vitamin B12, B12 complexed to transcobalamin as holotranscobalamin (HTCII), total homocysteine (tHcy), serum creatinine and estimated creatinine clearance (eCrCl) in 37 cancer patients presenting with newly diagnosed solid tumors. Serum HTCII was measured by the glass adsorption technique developed in this laboratory (Vu, T et al. Am J. Hem 42: 202–211 1993). Pearson’s r values were calculated for tHcy as a function of serum folate, total B12, HTCII, or eCrCl. R values reflect the degree of linear relationship between two variables. We found that 15 of 37 (40.5%) newly diagnosed and untreated cancer patients had serum homocysteine levels above 12 μM/L. The mean tHCY = 11.43 μM/L, median = 10.7 μM/L, range = 2.5 to 22.4 μM/L. One of the 36 (2.8%) patients for whom folate data was available had folate deficiency (folate = 4.2 ng/mL; pancreatic cancer). Mean folate = 19.35 ng/mL, median = 20.0 ng/mL, range = 4.2–40.2 ng/mL. Serum folate was only weakly inversely related to tHcy (r = −0.29551). Serum eCrCl was strongly inversely related to tHcy (r = −0.57927, p < 0.0002). Twenty-seven of 37 patients (73%) had a low creatinine clearance (