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ABSTRACTChemotherapy is the standard of care for most malignancies. Its tumor debulking effect in adjuvant or neoadjuvant settings is unquestionable, although secondary effects have been reported that paradoxically promote metastasis. Chemotherapy affects the hematopoietic precursors leading to myelosuppression, with neutropenia being the main hematological toxicity induced by cytotoxic therapy. We used renal and lung murine tumor models metastatic to the lung to study chemotherapy-induced neutropenia (CIN) in the metastatic process. Cyclophosphamide and doxorubicin, two myelosuppressive drugs, but not cisplatin, increased the burden of artificial metastases to the lung, by reducing neutrophils. This effect was recapitulated by treatment with anti-Ly6G, the selective antibody-mediated neutrophil depletion that unleashed the formation of lung metastases in both artificial and spontaneous metastasis settings. The increased cancer dissemination was reversed by granulocyte-colony stimulating factor-mediated boosting of neutrophils in combination with chemotherapy. CIN affected the early metastatic colonization of the lung, quite likely promoting the proliferation of tumor cells extravasated into the lung at 24–72 hours. CIN did not affect the late events of the metastatic process, with established metastasis to the lung, nor was there any effect on the release of cancer cells from the primary, whose growth was, in fact, somewhat inhibited. This work suggests a role of neutrophils associated to a common cancer treatment side effect and claims a deep dive into the relationship between chemotherapy-induced neutropenia and metastasis.

Restoration of grassland habitats useful for wildlife is an intervention often carried out in various marginal environments (such as some mountainous areas) where agriculture and grassland management have undergone deep changes in recent decades. To assess some of these interventions, a study was conducted in an Apennine reserve in Central Italy, where some grassland areas recovered through different techniques were identified, represented by shrub clearing followed by sowing of a forage mixture and shrub clearing alone, which were compared with natural areas on which no interventions were carried out. Several parameters related to the botanical composition and quality of the recovered pastoral resources were analysed. In addition, in three different experimental sites, further in-depth investigations were carried out to assess the actual animal frequentation and the impact of the intake of the wild animals present (mainly red deer) on the occurring vegetation. Results highlighted the importance of recovery interventions in these situations, the success of mechanical treatments (even if represented by clearing shrubs alone), and the real appreciation for the recovered areas by wildlife, whose utilisation on different vegetal species could be assessed, highlighting a diverse feeding behaviour for some taxa, compared to domestic animals.

Prolonged SARS-CoV-2 infections are widely described in immunosuppressed patients, but safe and effective treatment strategies are lacking. We aimed to outline our approach to treating persistent COVID-19 in patients with immunosuppression from different causes. In this case series, we retrospectively enrolled all immunosuppressed patients with persistent SARS-CoV-2 infections treated at our centers between March 2022 and February 2023. Patients received different sequential or combination regimens, including antivirals (remdesivir, nirmatrelvir/ritonavir, or molnupiravir) and/or monoclonal antibodies (mAbs) (tixagevimab/cilgavimab or sotrovimab). The main outcome was a complete virological response (negative SARS-CoV-2 RT-PCR on nasopharyngeal swabs) at the end of treatment. Fifteen patients were included as follows: eleven (11/15; 73%) with hematological disease and four (4/15; 27%) with recently diagnosed HIV/AIDS infection. Six patients (6/15; 40%) received a single antiviral course, four patients (4/15; 27%) received an antiviral and mAbs sequentially, and two patients (13%) received three lines of treatment (a sequence of three antivirals or two antivirals and mAbs). A combination of two antivirals or one antiviral plus mAbs was administered in three cases (3/15, 20%). One patient died while still positive for SARS-CoV-2, while fourteen (14/15; 93%) tested negative within 16 days after the end of treatment. The median time to negativization since the last treatment was 2.5 days. Both sequential and combination regimens used in this study demonstrated high efficacy and safety in the high-risk group of immunosuppressed patients.

Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific. Editor's summary: Baseline differences in the immune system between individuals are driven by both heritable and nonheritable, environmental factors. By analyzing endometrial and peripheral blood immune cells collected from monozygotic twins, Bister et al. measured the tissue-specific contributions of nonheritable effects on immune system variation. Although peripheral blood immune cells were largely shaped by genetics, environmental factors including hormonal contraception contributed more strongly to the variation in endometrial immune cells and soluble proteome. Together, these findings demonstrate that the human immune system can be highly variable and driven by nonheritable factors in a tissue-specific manner. —Claire Olingy [ABSTRACT FROM AUTHOR]

Earthworms have provided ancient cultures with food and sources of medicinal cures. Ayurveda, traditional Chinese medicine (TCM), and practices in Japan, Vietnam, and Korea have focused first on earthworms as sources of food. Gradually fostering an approach to potential beneficial healing properties, there are renewed efforts through bioprospecting and evidence-based research to understand by means of rigorous investigations the mechanisms of action whether earthworms are used as food and/or as sources of potential medicinal products. Focusing on earthworms grew by serendipity from an extensive analysis of the earthworm's innate immune system. Their immune systems are replete with leukocytes and humoral products that exert credible health benefits. Their emerging functions with respect to evolution of innate immunity have long been superseded by their well-known ecological role in soil conservation. Earthworms as inexpensive, noncontroversial animal models (without ethical concerns) are not vectors of disease do not harbor parasites that threaten humans nor are they annoying pests. By recognizing their numerous ecological, environmental, and biomedical roles, substantiated by inexpensive and more comprehensive investigations, we will become more aware of their undiscovered beneficial properties.

Host–microbiome interplay from birth is essential for immune imprinting and tuning. Live gut microbes and microbial‐derived metabolites regulate the development and modulation of the immune system, but whether microbial metabolites solely are sufficient to induce immune maturation remains unclear. Sterile faecal filtrates (FFT) were generated from murine gut contents. Newborn germ‐free (GF) mice were treated twice daily with FFT (GF‐FFT) or saline (GF‐NaCl) from post‐natal day 5 until 4 weeks of age. A third group of GF neonates were conventionalized by the transfer of caecal microbiota with live gut microbes. Host immune compartments were comprehensively immunophenotyped and systemically analysed in all available immune‐related organs using flow cytometry. Oral FFT was associated with reduced survival among neonates (n = 7/19; 36.8% mortality), while saline treatment was well tolerated (n = 1/17, 5.9% mortality). Four‐week‐old FFT‐treated pups were comparable in body weight to GF‐NaCl, and the major B‐cell, conventional T‐cell and unconventional T‐cell subsets were unchanged from saline‐treated mice. Live bacteria administered during early life induced clear changes in proportions of B cells, T cells and T‐cell subsets in all mucosal tissues and secondary lymphoid organs compared to GF‐FFT, including restoration of intestinal natural killer T (NKT) cells with characteristics similar to conventional pups. Our findings show that oral administration of a FFT made of microbial metabolites, antigens and bacteriophages alone is insufficient to induce normal immune development elicited by the presence of live bacteria. Reduced survival during neonatal FFT treatment suggests a potential bioactive attribute of sterile faecal filtrates. [ABSTRACT FROM AUTHOR]

Lipoptena fortisetosa and L. cervi are hematophagous ectoparasites belonging to the Hippoboscidae family and preferentially living on cervids. In recent years, they have received specific attention due to the great increase in the abundance of their host species, and to their medical and veterinary importance as possible vectors of pathogens harmful to humans and animals. The aim of this study was to investigate the parasitism level of both of these flies on their main hosts in Italy, which are red deer, fallow deer, and roe deer, and to highlight a possible preference for a species, sex, or age class among the hosts. Deer keds were collected by examining 326 cervids hunted in the Tuscan-Emilian Apennines. Outcomes showed that L. fortisetosa has greatly spread throughout the study area, where it competes with the autochthonous L. cervi. Moreover, red deer was the favored host species of both ectoparasites, while different preferences for host sex and age classes were observed in the two hippoboscids. The regular monitoring of deer ked populations, especially the allochthonous L. fortisetosa, which is continuously spreading in Europe, is recommended to expand the knowledge on these parasitic species that are potentially dangerous to public health.

The hippoboscid Lipoptena fortisetosa Maa, 1965 is a hematophagous ectoparasite of cervids that can bite humans. This fly is expanding its geographical range and is of concern for animal and human health since it can potentially harbour harmful microorganisms. This study was aimed at characterizing the bacterial communities of L. fortisetosa in its different life‐cycle stages. Pupae and wingless adults were collected from cervids hunted in Tuscan‐Emilian Apennines (central Italy) and pooled into groups of 10 by life stage (30 individual pupae; 1420 individual wingless adults). Winged flies were caught by sweep netting and separated into five pools of 10 insects. After DNA extraction, the bacterial content of each pool was analysed using 16 S metabarcoding. Results revealed that the composition and relative abundance of different taxa greatly differed in the three analysed groups. Wingless adults showed a high abundance of Bartonella (33.07%), which is almost absent in winged flies and pupae. Among the detected pathogens, four genera of concern for human health were found: Bartonella, Moraxella, Mycobacterium and Rickettsia. Interestingly reads similar to Bartonella bovis, Moraxella osloensis and Arsenophonus lipopteni Operational Taxonomic Unit (OTUs) were detected. These findings suggest the possible role of L. fortisetosa as a reservoir of pathogenic microorganisms, confirming the need for further investigation to ascertain its vectorial capacity. [ABSTRACT FROM AUTHOR]

Morphometric studies on European red deer (Cervus elaphus L.) living in sub-Mediterranean areas are rare. In this paper, we provide the first morphometric description of red deer from Apennine living in Prato Province, as well as a description of its skeletal growth pattern. We analysed 18 body, cranial and antler measurements from 905 deer carcasses, collected during 12 hunting seasons (2000–2012). The body size of red deer from Prato appeared comparable to that of other populations from Northern Apennine and Central Alps. A significant variation in weight during the hunting season was detected only in adult stags: they were estimated to lose 23% of their eviscerated body weight from the beginning of the rutting season until the end of winter. The relationship between eviscerated body weight (EW) and whole body weight (WW) was highly significant in both sexes within every age class (R2 always higher than 0.75), thus linear regressions were assessed in order to estimate EW from WW, allowing to complete datasets when such information is missing. Growth equations were utilised to describe the development of a subset of skeletal measures (height at shoulder, hind foot length, mandible length, head–trunk length) commonly collected on hunted cervids. Hind foot length was the measure which first ceased to grow and with the highest growth constant; although the relationship between cohort hind foot length and environmental, climatic and demographic variables has to be tested for red deer from Apennine, these bones appeared a suitable biological indicator for long-term monitoring of the species.

The abandonment of pastures often leads to a remarkable deterioration of grasslands, caused by the spread of intrusive, herbaceous and woody species which reduces the general quality of pastures. Different treatments aimed at improving the grassland and enhancing the forage quality of herbaceous resources have been developed to face this problem. We report the results of a five-year experiment conducted in a protected area of central Italy (the “Laghi di Suviana e Brasimone” regional park) on an abandoned pasture inside a beech forest encroached by intrusive species (mainly bracken). We analyzed the effect on sward’s specific composition and grazing value of two agronomic factors: (i) the establishment method (ploughing followed by sowing of a forage mixture versus no intervention), and (ii) the number of cuts performed on vegetation during the growing season (0, 1 or 2 cuts). Plots were arranged according to a split-split-plot experimental design with three replications, with the sampling dates as the main factor, the establishment technique as the subplot factor, and the number of cuts as the sub-subplot factor. In each plot, data were recorded once a month from June to September every year from 2006 to 2010, in order to assess the botanical composition and the quality of the sward. The main pastoral and botanical parameters of pastures were significantly affected by both cutting and sowing. Establishment by sowing significantly reduced the presence of bracken, even with no cuts, with strong effects on the qualitative value of the pasture. A single cut resulted in an efficient recovery of the pasture as compared to cutting twice, especially in sown plots. Our results confirmed that the regular and continued maintenance of the recovered areas is crucial to ensure the long-term preservation of the results achieved by the improvements.