IDENTIFYING PREDICTIVE MARKERS OF RESPONSE AND RESISTANCE TO POTENT MULTI-AGENT HER2-TARGETED THERAPY

Background: Dual HER2 blockade with lapatinib plus trastuzumab without chemotherapy resulted in a substantial pathologic complete response (pCR) rate in HER2+ breast cancer patients (TBCRC006). Aberrant activation of the PI3K pathway as well as levels of tumor infiltrating lymphocytes (TILs) at diagnosis has been shown to be associated with response to HER2 targeted therapy. However, the results from these clinical trials are confounded by the co-administration of chemotherapy. In this study, we investigated the predictive value of PI3K-pathway activation and TILs in patients receiving neoadjuvant HER2 targeted therapy without chemotherapy. Methods: Pre-treatment biopsies from patients enrolled in the TBCRC006 trial were used for the aims of this study. PTEN expression status and PIK3CA mutations were assessed by immunohistochemistry and targeted sequencing of tumor DNA, respectively. Hematoxylin and eosin (H&E)-stained slides were evaluated for the % of stromal TILs; a threshold of 60% was used to define high TILs. Single formalin-fixed paraffin-embedded slides from 10 cases were co-stained for CD4, CD8, CD20, CD68, FoxP3, cytokeratin, and DAPI by multiplexed immunofluorescence (m-IF) using PerkinElmer Opal system. Multispectral imaging and digital analysis to visualize and quantify specific immune infiltrates were performed using PerkinElmerVectra system. The results were correlated with pathologic complete response (pCR). Results: Of the 64 evaluable patients, tumor tissue was available from 59 patients for PTEN immunohistochemistry, and DNA was available from 38 cases for mutation analysis. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p=0.04). PIK3CA mutations were identified in 12/38 tumors (32%) and were independent of ER or PTEN expression. No patient whose tumor harbored a PIK3CA mutation achieved pCR (p=0.07). When considered together (35 cases), 0/19 cases (0%) with a PIK3CA mutation and/or PTEN low expression had a pCR compared to 5/16 cases (31%) with PI3KCA wild type and high PTEN (p=0.01). TILs evaluation was available for 59 of the 64 patients who were evaluable for pathologic response. Twelve of 59 pts (20%) exhibited High TILs. The pCR rate was numerically higher in high-TILs compared to low-s-TILs (50% vs. 19%, P = 0.057). Multispectral imaging successfully captured and quantified multiple immune cell types in all the so far m-IF-stained samples. The density of stromal TILs (calculated as the total number of cells positive for the above immune markers/mm2) significantly correlated with % of stromal TILs evaluated on the H&E-stained slides (r = 0.76, P = 0.01). Conclusion: PI3K pathway hyperactivation is associated with resistance to lapatinib and trastuzumab without chemotherapy. If externally confirmed, future studies should investigate targeting PI3K/Akt/mTOR, in addition to HER2, in patients with HER2-positive tumors and evidence of aberrant downstream PI3K pathway activation. High levels of stromal TILs were associated with a numerically higher pCR rate than low stromal TILs in patients with HER2+ breast cancer treated with anti-HER2 agents without chemotherapy. However, the p-value did not reach statistical significance. Characterizing TILs with m-IF is feasible and may help correlate various TIL subpopulations with response to treatment

Nab-paclitaxel for the management of triple-negative metastatic breast cancer: a case study

The optimal sequence of systemic chemotherapy in metastatic breast cancer (MBC) is unknown. We report the case of a woman who was successfully treated with nanoparticle albumin-bound (nab)-paclitaxel for triple negative MBC in our institution. In November 2008, a 48-year-old woman underwent surgical treatment for a triple negative invasive ductal breast cancer and subsequently received adjuvant chemotherapy with fluorouracil/epirubicin/cyclophosphamide and radiotherapy. Sixteen months after surgery, she presented with a left chest wall metastatasis. The patient received combination therapy with conventional paclitaxel (90 mg/m² weekly for 3 out of 4 weeks [QW 3/4]) and bevacizumab (10 mg/kg every 2 weeks [Q2W]) as first-line treatment for MBC (six cycles; March to September 2010) and achieved a partial response at the metastatic site. Bevacizumab monotherapy was continued until disease progression (April 2011) with the development of a single infraclavicular lymph node metastasis and an increase in the dimensions of the left chest wall lesion. From May to December 2011, the patient received nab-paclitaxel 260 mg/m² every 3 weeks (Q3W) as second-line treatment (11 cycles). After three cycles, the left chest wall lesion and the infraclavicular lymph node metastasis were undetectable and the patient was considered to have achieved a complete response. Treatment was well tolerated with no significant toxicity or need for dose reduction. Given our case, here we review the clinical evidence and discuss the potential role of nab-paclitaxel for the treatment of triple negative MBC, a subgroup typically characterized as having aggressive disease and limited treatment options

Quaterpyridine Ligands for Panchromatic Ru(II) Dye Sensitizers

A new general synthetic access to carboxylated quaterpyridines (qpy), of interest as ligands for panchromatic dyesensitized solar cell organometallic sensitizers, is presented. The strategic step is a Suzuki−Miyaura cross-coupling reaction, which has allowed the preparation of a number of representative unsubstituted and alkyl and (hetero)aromatic substituted qpys. To bypass the poor inherent stability of 2-pyridylboronic acid derivatives, we successfully applied N-methyliminodiacetic acid (MIDA) boronates as key reagents, obtaining the qpy ligands in good yields up to (quasi)gram quantities. The structural, spectroscopic (NMR and UV−vis), electrochemical, and electronic characteristics of the qpy have been experimentally and computationally (DFT) investigated. The easy access to the bis-thiocyanato Ru(II) complex of the parent species of the qpy series, through an efficient route which bypasses the use of Sephadex column chromatography, is shown. The bis-thiocyanato Ru(II) complex has been spectroscopically (NMR and UV−vis), electrochemically, and computationally investigated, relating its properties to those of previously reported Ru(II)−qpy complexes.“This document is the Accepted Manuscript version of a Published Work that appeared in final form in [The Journal of Organic Chemistry], copyright © American Chemical Society after peer review and technical editing by the publisher

Use of Almond Skins to Improve Nutritional and Functional Properties of Biscuits: An Example of Upcycling

Upcycling food industry by-products has become a topic of interest within the framework of the circular economy, to minimize environmental impact and the waste of resources. This research aimed at verifying the effectiveness of using almond skins, a by-product of the confectionery industry, in the preparation of functional biscuits with improved nutritional properties. Almond skins were added at 10 g/100 g (AS10) and 20 g/100 g (AS20) to a wheat flour basis. The protein content was not influenced, whereas lipids and dietary fiber significantly increased (p < 0.05), the latter meeting the requirements for applying "source of fiber" and "high in fiber" claims to AS10 and AS20 biscuits, respectively. The addition of almond skins altered biscuit color, lowering L* and b* and increasing a*, but improved friability. The biscuits showed sensory differences in color, odor and textural descriptors. The total sum of single phenolic compounds, determined by HPLC, was higher (p < 0.05) in AS10 (97.84 µg/g) and AS20 (132.18 µg/g) than in control (73.97 µg/g). The antioxidant activity showed the same trend as the phenolic. The p-hydroxy benzoic and protocatechuic acids showed the largest increase. The suggested strategy is a practical example of upcycling when preparing a health-oriented food product

Effectiveness of Oat-Hull-Based Ingredient as Fat Replacer to Produce Low Fat Burger with High Beta-Glucans Content

Low-fat beef burgers with high beta-glucan content was obtained using a gel made from an oat-hull-based ingredient as fat replacer. Two levels of fat substitution were considered: 50% (T1) and 100% (T2). The nutritional composition, cooking yield, textural properties, color characteristics and consumer preference were evaluated, in comparison with a burger without fat replacer (CTRL). After cooking, T2 burger showed a significant increase in the cooking yield and a very low lipid content (3.48 g 100 g-1) as well as a level of beta-glucans per single portion (2.96 g 100 g-1) near the recommended daily intake. In T1 burger, the decrease of lipid content was mitigated during the cooking process, because the beta-glucans added had a fat-retaining effect. Compared to CTRL, replacing fat led to a softer texture of cooked burgers evaluated by Texture Profile Analysis. The differences in color, significant in raw burgers, were smoothed with cooking. The consumer evaluation, carried out according to the duo-trio test, highlighted significant differences between CTRL and T2 burgers in terms of odor, taste, color and texture. The consumers expressed a higher preference for the T2 burger, probably due to its softer texture and greater juiciness

Use of Almond Skins to Improve Nutritional and Functional Properties of Biscuits: An Example of Upcycling

Upcycling food industry by-products has become a topic of interest within the framework of the circular economy, to minimize environmental impact and the waste of resources. This research aimed at verifying the effectiveness of using almond skins, a by-product of the confectionery industry, in the preparation of functional biscuits with improved nutritional properties. Almond skins were added at 10 g/100 g (AS10) and 20 g/100 g (AS20) to a wheat flour basis. The protein content was not influenced, whereas lipids and dietary fiber significantly increased (p < 0.05), the latter meeting the requirements for applying “source of fiber” and “high in fiber” claims to AS10 and AS20 biscuits, respectively. The addition of almond skins altered biscuit color, lowering L* and b* and increasing a*, but improved friability. The biscuits showed sensory differences in color, odor and textural descriptors. The total sum of single phenolic compounds, determined by HPLC, was higher (p < 0.05) in AS10 (97.84 µg/g) and AS20 (132.18 µg/g) than in control (73.97 µg/g). The antioxidant activity showed the same trend as the phenolic. The p-hydroxy benzoic and protocatechuic acids showed the largest increase. The suggested strategy is a practical example of upcycling when preparing a health-oriented food product.info:eu-repo/semantics/publishedVersio

Rheological properties of dry-fractionated mung bean protein and structural, textural, and rheological evaluation of meat analogues produced by high-moisture extrusion cooking

A closed cavity rheometer was used to study the rheology of dry-fractionated mung bean protein –DFMB– (55% protein d.m.). Then, the high-moisture extrusion cooking at 40% and 50% moisture contents and different temperatures (115, 125, 135 and 145 °C) was performed, investigating the impact on structural, textural, and rheological properties of extrudates. When subjected to a temperature ramp (40–170 °C), DFMB showed an increase of G* from 70 °C, as a consequence of starch gelatinization and protein gelation. The peak, indicating the end of aggregation reactions, was at 105 °C and 110 °C for DFMB at 50% and 40% moisture content, respectively. The time sweep analysis described the protein behavior in no-shear/shear conditions, highlighting a more pronounced effect of the temperatures compared to moisture content. During the extrusion cooking, the temperature increase led to a decrease of pressure, indicating a reduction of the melt viscosity. The microstructure of the extrudates showed a more pronounced anisotropic profile when higher temperatures were applied. Hardness, chewiness, and cohesion were directly correlated with the temperature, which also affected the rheological properties of extrudates. A combination of textural and rheological analyses can offer a clear overview of the structural characteristics of meat analogues

Combination of Cytotoxic Drugs for Patients with HER2-Negative Metastatic Breast Cancer

In the last few decades the approach to metastatic breast cancer (MBC) treatment using chemotherapy, either as single or combination agents, has been largely studied and a wide spectrum of therapeutic options is now available. Anthracyclines and taxanes remain the cornerstone of treatment in this setting. The choice of combination chemotherapy versus monochemotherapy is still open to debate since results from clinical trials are, unfortunately, conflicting. Despite improvements in response and disease-free survival rates, there has been no overall survival benefit reported although toxicity is increased. Therefore, based on available data, clinical decision-making for a busy practitioner should consider not only patient/tumor characteristics and the potential benefits of treatments, but also their toxicity profiles and patient preferences. Novel cytotoxic compounds have been approved for clinical use and combination regimens incorporating these agents may bring new treatment opportunities for MBC patients. In this review, we summarize the main achievements and the currently available and future combinations of cytotoxic drugs for patients with HER2-negative MBC

Dry fractionation as a promising technology to reuse the physically defected legume-based gluten-free pasta

Dry fractionation was applied to the legume-based pasta (yellow lentils:whole rice 90:10 w:w) discarded for physical defects. After the air classification, the fine fraction showed a 33% increment of the protein content compared to the raw material, with a 21% yield. The scanning electron micrographs revealed the presence of protein–starch complexes and broken starch granules which led to a low protein separation efficiency. The fine fraction showed interesting nutritional features due to the high concentration of the essential micronutrients Zn (43.3 mg kg−1) and Fe (72.6 mg kg−1). However, also the alpha-galactosides were enriched into the same fraction. The two fractions, fine and coarse, were both characterised by elevated water absorption capacity, with significantly higher values in the fine one. Finally, the gelling capacity varied among the fractions, being influenced by the protein content. Overall, these ingredients could be used to fortify the protein and the essential mineral contents of bakery products, sauces, and creams