Treatment selection for patients with equivocal HER2 status and in luminal versus HER2-enriched disease

Equivocal HER2 status has been variably defined in the past, and its clinical implications have long been debated. In the 2018 focused update, ASCO/CAP guidelines recommended that tumours with double-equivocal (by immunohistochemistry and in situ hybridization assays) HER2 status should be considered HER2-negative due to the lack of evidence for any benefit of HER2-targeted therapy. The biology and the response to systemic therapies of tumours co-expressing HR and HER2 is quite complex. There is an extensive bi-directional cross-talk between these 2 pathways, that may result in both intrinsic and acquired resistance to endocrine agents, as well as in lower sensitivity to HER2-targeted therapies. In fact, neoadjuvant studies indicate that pCR rates are significantly lower in HER2-positive/ER-positive than ER-negative tumours, regardless the type of HER2 targeted treatment. The recent identification of different subtypes of HER2-positive breast cancer, according to the co-expression of HR and/or the molecular (intrinsic) subtyping, has prompted a renewed interest for clinical studies aimed at better tailoring the systemic therapy for these patients. A subgroup of them might not need chemotherapy if treated with dual HER2 blockade, and this option has been tested in a number of neo-adjuvant trials. In addition, triple targeting of HR, HER2, and CDK4/6 pathways simultaneously may be an effective treatment and overcome the drug resistance mechanisms that are typical of the disease. Finally, HER2-positive breast cancer may well benefit from immunotherapeutic interventions with anti-programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) agents

Ileal pneumatosis

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Reduced coherence in double-slit diffraction of neutrons

In diffraction experiments with particle beams, several effects lead to a fringe visibility reduction of the interference pattern. We theoretically describe the intensity one can measure in a double-slit setup and compare the results with the experimental data obtained with cold neutrons. Our conclusion is that for cold neutrons the fringe visibility reduction is due not to decoherence, but to initial incoherence.Comment: 4 pages LaTeX, 2 figure

Collective behaviour without collective order in wild swarms of midges

Collective behaviour is a widespread phenomenon in biology, cutting through a huge span of scales, from cell colonies up to bird flocks and fish schools. The most prominent trait of collective behaviour is the emergence of global order: individuals synchronize their states, giving the stunning impression that the group behaves as one. In many biological systems, though, it is unclear whether global order is present. A paradigmatic case is that of insect swarms, whose erratic movements seem to suggest that group formation is a mere epiphenomenon of the independent interaction of each individual with an external landmark. In these cases, whether or not the group behaves truly collectively is debated. Here, we experimentally study swarms of midges in the field and measure how much the change of direction of one midge affects that of other individuals. We discover that, despite the lack of collective order, swarms display very strong correlations, totally incompatible with models of noninteracting particles. We find that correlation increases sharply with the swarm's density, indicating that the interaction between midges is based on a metric perception mechanism. By means of numerical simulations we demonstrate that such growing correlation is typical of a system close to an ordering transition. Our findings suggest that correlation, rather than order, is the true hallmark of collective behaviour in biological systems.Comment: The original version has been split into two parts. This first part focuses on order vs. correlation. The second part, about finite-size scaling, will be included in a separate paper. 15 pages, 6 figures, 1 table, 5 video

Symbiotic bacteria inhabiting tephritid flies: a worldwide specific interaction

Several insect lineages have evolved mutualistic associations with their symbiotic bacteria. This is the case of some members of Tephritinae, the most specialized subfamily of fruit flies (Diptera: Tephritidae), harboring co-evolved and vertically transmitted bacterial symbionts in their midgut, known as ‘Candidatus Stammerula spp.’. In the tephritid fly Bactrocera oleae, the major olive pest, symbionts are located in the oesophageal bulb, a diverticulum of the fly head, and designated as ‘Candidatus Erwinia dacicola’. This research, based on two main studies, is focused on different aspects of the relationships between species of the family Tephritidae and their nonculturable symbiotic bacteria. The first study investigated the presence of specific symbiotic bacteria in 15 of the 25 described endemic tephritids of the Hawaiian Archipelago, which represent a spectacular example of adaptive radiation, and their molecular relationships with symbionts of non-Hawaiian tephritids. Moreover the concordant evolution between host and symbiont phylogenies was tested. A specific symbiont was detected through PCR assays in all endemic individuals analyzed and it was designated as ‘Candidatus Stammerula trupaneae’ as it was included in Ca. Stammerula spp. monophyletic clade. The phylogeny of the insect host was reconstructed based on two regions of the mitochondrial DNA (16S rDNA and COI-tRNALeu-COII), while the bacterial 16S rRNA was used for the symbiont analysis. Host and symbiont phylogenies were then compared and evaluated for patterns of cophylogeny and strict cospeciation. Topological congruence between Hawaiian Tephritinae and their symbiotic bacteria phylogenies suggests a limited, but significant degree of host-symbiont cospeciation. The character evolution of three host traits, as island location, host lineage, and host tissue attacked, was finally reconstructed based on the symbiont phylogenies under the hypothesis of cospeciation. The second study surveys the genetic variability of the olive fly symbiont, Ca. Erwinia dacicola, together with the patterns of genetic differentiation of B. oleae, over a large area of its geographical distribution, including most regions of the Mediterranean area, plus South Africa, California and Pakistan. Three bacterial haplotypes, showing a significative geographic distribution, were identified and the co-existence of different Ca. E. dacicola haplotypes in a single fly was never found. Our results reveal the presence of three symbiont haplotypes with a significant phylogeographic distribution related to the territory. In the Mediterranean populations only two bacterial lineages (htA and htB), previously recovered in Italian olive fly populations, have been found, showing a significative East-West genetic differentiation. The South African and Californian olive fly populations were represented only by one of these two lineages, respectively htA and htB. Moreover, a new haplotype (htC) was detected exclusively in the Pakistani population. On the other hand, a high degree of mitochondrial genetic variability with a substantial phylogeographic differentiation has been observed in the B. oleae populations analyzed, revealing the presence of 39 insect haplotypes. Symbiont and host haplotypes were then compared and a significant correlation was found suggesting the predominant presence of vertical transmission. Moreover, the bacterial haplotypes distribution seems to be more related to the territory than the numerous insect host haplotypes, representing an useful tool to reconstruct the debated olive fly’s historical origin

Finite-size scaling as a way to probe near-criticality in natural swarms

Collective behaviour in biological systems is often accompanied by strong correlations. The question has therefore arisen of whether correlation is amplified by the vicinity to some critical point in the parameters space. Biological systems, though, are typically quite far from the thermodynamic limit, so that the value of the control parameter at which correlation and susceptibility peak depend on size. Hence, a system would need to readjust its control parameter according to its size in order to be maximally correlated. This readjustment, though, has never been observed experimentally. By gathering three-dimensional data on swarms of midges in the field we find that swarms tune their control parameter and size so as to maintain a scaling behaviour of the correlation function. As a consequence, correlation length and susceptibility scale with the system's size and swarms exhibit a near-maximal degree of correlation at all sizes.Comment: Selected for Viewpoint in Physics; PRL Editor's Suggestio

Development and validation of a novel SNP panel for the genetic characterization of Italian chicken breeds by next-generation sequencing discovery and array genotyping

Abstract The aim of this study was to compare the intra and inter genetic variability and population structure of 7 indigenous chicken breeds of the Veneto region, through a novel panel of 64 SNP, each located in an exonic region and mostly on different chromosomes. A total of 753 blood samples from 7 local chicken breeds (Ermellinata di Rovigo, Millefiori di Lonigo, Polverara, Pepoi, Robusta Lionata, Robusta Maculata, and Padovana) was collected and analyzed. Two strains of Polverara (Nera and Bianca) and Padovana (Dorata and Camosciata) were included in the study. The observed heterozygosity ranged from 0.124 (Pepoi) to 0.244 (Ermellinata di Rovigo), and the expected heterozygosity varied from 0.132 (Millefiori di Lonigo) to 0.300 (Ermellinata di Rovigo). Global FIS results (0.114) indicated a low-medium inbreeding effect, with values ranging from 0.008 (Millefiori di Lonigo) to 0.223 (Ermellinata di Rovigo). Pairwise FST values (0.167) for all populations ranged from 0.020 (Polverara Nera and Polverara Bianca) to 0.193 (Robusta Lionata and Polverara Nera), indicating that the studied breeds were genetically highly differentiated. The software STRUCTURE was used to detect the presence of population substructures, and the most probable number of clusters (K) of the 10 chicken populations was at K = 8. The affiliation was successful in all Veneto chicken breeds. The present SNP marker results, compared with previous data obtained using microsatellites, provided a reliable estimate of genetic diversity within and between the studied breeds, and demonstrated the utility of the proposed panel as a rapid, efficient, and cost-effective tool for periodical monitoring of the genetic variability among poultry populations. In addition, the present SNP panel could represent a resource for a systematic approach with relevant impact on breeding program decisions and could turn out to be a reliable tool for genetic traceability of indigenous chicken meat. Adoption of a periodical monitoring system of genetic diversity is a fundamental tool in conservation actions and should increase the value of typical and niche products

Pegylated liposomal doxorubicin in combination with low-dose metronomic cyclophosphamide as preoperative treatment for patients with locally advanced breast cancer.

Abstract Aim To evaluate the role of pegylated liposomal doxorubicin with low-dose metronomic cyclophosphamide as primary systemic treatment in locally advanced breast cancer. Patients and Methods The activity and safety of intravenous pegylated liposomal doxorubicin 20 mg sqm−1 biweekly for eight courses in combination with metronomic cyclophosphamide 50 mg day−1 orally were evaluated in 29 patients with locally advanced breast cancer who were not suitable to receive a standard chemotherapy due to age or co-morbidities or who asked for a regimen with low incidence of toxic effects irrespective of age. Results The rate of breast-conserving surgery was 44.8%. Eighteen patients (62.1%) achieved a partial response (including one pathological complete response), 10 (34.5%) a stable disease and one patient experienced a progressive disease. Treatment was well tolerated, with no grade 4 toxicities, and with grade 3 skin toxicity in three patients and hand–foot syndrome in four patients. Conclusion The regimen was well tolerated but with limited activity in the preoperative setting. Other options (e.g., endocrine therapy in estrogen receptor -positive disease) should be considered in locally advanced breast cancer patients who are not suitable to receive a standard chemotherapy

Prospective role of cefiderocol in the management of carbapenem-resistant Acinetobacter baumannii infections: Review of the evidence

Carbapenem-resistant Acinetobacter baumannii (CRAB) has been classified by the World Health Organization as being in the critical category of pathogens requiring urgent new antibiotic treatment options. Cefiderocol, the first approved siderophore cephalosporin, was designed for the treatment of carbapenem-resistant Gram-negative pathogens, particularly the non-fermenting species A. baumannii and Pseudomonas aeruginosa. Cefiderocol is mostly stable against hydrolysis by serine β-lactamases and metallo-β-lactamases, which are leading causes of carbapenem resistance. This review collates the available evidence on the in vitro activity, pharmacokinetics/pharmacodynamics, and efficacy and safety of cefiderocol, and outlines its current role in the management of CRAB infections. In vitro surveillance data show susceptibility rates of \u3e90% for cefiderocol against CRAB isolates as well as in vitro synergism with a variety of antibiotics recommended in guidelines. Clinical efficacy of cefiderocol monotherapy against CRAB infections has been demonstrated in the descriptive, open-label CREDIBLE-CR and the non-inferiority, double-blind APEKS-NP randomised clinical trials as well as in real-world cases in patients with underlying health problems. To date, the frequency of on-therapy development of cefiderocol resistance in A. baumannii appears to be low, but monitoring is highly recommended. Within current treatment guidelines for moderate-to-severe CRAB infections, cefiderocol is recommended for infections in which other antibiotics failed and in combination with other active antibiotics. In vivo pre-clinical data support the combination of sulbactam or avibactam with cefiderocol to enhance efficacy and to suppress the emergence of cefiderocol resistance. The benefit of combination therapy in the clinical setting is yet to be determined in prospective studies