Tumor’host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds

Targeting of the tumor stroma, including the tumor vasculature, represents a new frontier in the treatment of malignancy. Preclinical studies and clinical experiences have established that stroma-directed novel agents must be combined with conventional therapies in order to achieve relevant therapeutic efficacy. Here we review our preclinical experience on combinations of paclitaxel with a tyrosine kinase receptor inhibitor of angiogenesis (SU6668) and a vascular disrupting agent (VDA, ZD6126), and discuss the critical factors that determine the outcome of these treatments. We also analyze the relevance of the intrinsic sensitivity of the tumor to the drugs, as well as the possibility that the two combined agents synergistically affect the vasculature or independently target the host and the tumor compartments. Finally, we discuss the need to carefully optimize scheduling and sequencing, through the use of reliable end points, in order to avoid negative pharmacological interactions and to improve the antineoplastic efficacy of paclitaxel-based combination treatments.     

Assessment of the Impact of a Toll-like Receptor 2 Agonist Synthetic Lipopeptide on Macrophage Susceptibility and Responses to African Swine Fever Virus Infection

Toll-like receptor 2 (TLR2) ligands are attracting attention as prophylactic and immunopotentiator agents against pathogens, including viruses. We previously reported that a synthetic diacylated lipopeptide (Mag-Pam2Cys_P48) polarized porcine macrophages towards a proinflammatory antimicrobial phenotype. Here, we investigated its role in modulating monocyte-derived macrophage (moMΦ) responses against African swine fever virus (ASFV), the etiological agent of one of the greatest threats to the global pig industry. Two ASFV isolates were compared: the attenuated NH/P68 and the virulent 26544/OG10. No effect on virus infection nor the modulation of surface markers’ expression (MHC I, MHC II DR, CD14, CD16, and CD163) were observed when Mag-Pam2Cys_P48 treated moMΦ were infected using a multiplicity of infection (MOI) of 1. Mag-Pam2Cys_P48 treated moMΦ released higher levels of IL-1α, IL-1β, IL-1Ra, and IL-18 in response to infection with NH/P68 ASFV compared to 26544/OG10-infected and mock-infected controls. Surprisingly, when infected using a MOI of 0.01, the virulent ASFV 26544/OG10 isolate replicated even slightly more efficiently in Mag-Pam2Cys_P48 treated moMΦ. These effects also extended to the treatment of moMΦ with two other lipopeptides: Mag-Pam2Cys_P80 and Mag-Pam2Cys_Mag1000. Our data suggested limited applicability of TLR2 agonists as prophylactic or immunopotentiator agents against virulent ASFV but highlighted the ability of the virulent 26544/OG10 to impair macrophage defenses.     

Effects on Serum Inflammatory Cytokines of Cholecalciferol Supplementation in Healthy Subjects with Vitamin D Deficiency

The effects of different cholecalciferol supplementation regimens on serum inflammatory cytokines in healthy subjects with vitamin D deficiency are still lacking. This is a single-center, open-label, randomized, parallel group study involving healthy subjects deficient in vitamin D (baseline 25OHD < 20 ng/mL) receiving oral cholecalciferol with three different dosing regimens: Group A: 10,000 IU/day for 8 weeks followed by 1000 IU/day for 4 weeks; Group B: 50,000 IU/week for 12 weeks and Group C: 100,000 IU every other week for 12 weeks. IL-17A, IL-6, IL-8, IL-10, IL-23 and TNFα were measured at baseline and at week 4, 8, 12, and 16. 75 healthy subjects were enrolled (58.7% female), with an average age of 34.1 ± 10.2 years. No statistical differences were observed among groups at baseline for either IL-6, IL-17A, IL-23, IL-8 or IL-10 at any time point; TNFα was indetectable. Concerning the whole sample, the time trend analysis showed a statistically significant linear trend for decreasing values over the treatment period for IL-6 (p = 0.016) and IL-17A (p = 0.006), while no significant time trends were observed for the other teste cytokines. No significant differences were found in the serum concentrations of the tested cytokines between week 12 and week 16. In young healthy individuals deficient in vitamin D, cholecalciferol administration showed a decrease in the serum IL-6 and IL-17A concentrations, without marked differences using the three regimens.     

Extra-Nodal Lymphomas of the Head and Neck and Oral Cavity: A Retrospective Study

Disease Overview: Lymphomas, both Hodgkin’s and non-Hodgkin’s lymphomas, are one of the most common cancers in the head and neck area. The extra-nodal variant of lymphoma is rare, but it is the most common non-Hodgkin’s lymphoma (ENHL). Furthermore, it is difficult to diagnose due to its non-specific clinical and radiological features, which can mimic other benign or malignant clinical manifestations. The study: This retrospective study involved 72 patients affected by head and neck ENHL in the period between 2003 and 2017. All patients underwent a diagnostic-therapeutic procedure according to the guidelines, and a 5-year follow-up. Based on the location of the swelling at the time of diagnosis, patients were divided into two groups: oral and non-oral ENHLs. Statistical analysis was performed using Kaplan–Meier analysis with the log-rank test. In addition, Fisher’s exact test was applied to the two groups to evaluate and compare variances (the acceptable significance level was set at p < 0.05). Conclusion: ENHL with oral localization is much more aggressive than ENHL with non-oral localization, with a death rate of 40% (versus 4.76 for the non-oral one). In fact, between the two groups, there is a statistically significant difference in mortality, with a p-value of 0.0001 and 0.0002, respectively.     

HE4 Tissue Expression as A Putative Prognostic Marker in Low-Risk/Low-Grade Endometrioid Endometrial Cancer: A Review

Low-grade stage I endometrioid endometrial carcinomas should have an excellent prognosis, but a small subset of these cancers can relapse. The search for putative immunohistochemical prognostic markers for relapse in low-risk/low-grade endometrioid endometrial cancers remains open. Among the candidate molecules that may implicate the roles of immunohistochemical risk markers, we focused our attention on human epididymis protein 4 (HE4) after a review of the literature. Few authors have devoted themselves to this topic, and none have found a correlation between the tissue expression of HE4 and the molecular classification of endometrial cancer. Five different variants of HE4 mRNA and multiple protein isoforms of HE4 were identified many years ago, but current HE4 assays only measure the total HE4 expression and do not distinguish the different proteins encoded by different mRNA variants. It is important to have an approach to distinguish specific variants in the future.     

The Influence of Sociodemographic Factors,Lifestyle, and Risk Perception on Dietary Patterns in Pregnant Women Living in Highly Contaminated Areas: Data from the NEHO Birth Cohort

During pregnancy, maternal nutrition and lifestyle play a critical role in influencing fetal development and newborn health outcomes. The aim of this study is to investigate the factors influencing the adherence to dietary patterns in pregnant women living in highly contaminated areas, and whether women with higher environmental risk perception manifest different nutritional behaviors during pregnancy. Food consumption data on 816 pregnant women from the Neonatal Environment and Health Outcomes (NEHO) residential birth cohort were analyzed. Dietary patterns were computed by principal component analysis. A multinomial logistic regression was also applied to identify sociodemographic, lifestyle, and pregnancy-related determinants of adherence to dietary patterns during pregnancy. Three patterns of food consumption—explaining 24.9% of the total variance—were identified as “prudent”, “high energy”, and “vegetarian” patterns. Results suggest that food choices during pregnancy follow a social gradient and align with other health behaviors during pregnancy: older, better educated, and physically active women with higher risk perception are more likely to follow healthier dietary patterns. Knowledge about what is eaten can contribute to dietary choices. Interventions to improve the prenatal nutrition knowledge of pregnant women are needed, especially concerning younger mothers and those with lower educational levels.     

Modifications of Chest CT Body Composition Parameters at Three and Six Months after Severe COVID-19 Pneumonia: A Retrospective Cohort Study

We aimed to describe body composition changes up to 6–7 months after severe COVID-19 and to evaluate their association with COVID-19 inflammatory burden, described by the integral of the C-reactive protein (CRP) curve. The pectoral muscle area (PMA) and density (PMD), liver-to-spleen (L/S) ratio, and total, visceral, and intermuscular adipose tissue areas (TAT, VAT, and IMAT) were measured at baseline (T0), 2–3 months (T1), and 6–7 months (T2) follow-up CT scans of severe COVID-19 pneumonia survivors. Among the 208 included patients (mean age 65.6 ± 11 years, 31.3% females), decreases in PMA [mean (95%CI) −1.11 (−1.72; −0.51) cm²] and in body fat areas were observed [−3.13 (−10.79; +4.52) cm² for TAT], larger from T0 to T1 than from T1 to T2. PMD increased only from T1 to T2 [+3.07 (+2.08; +4.06) HU]. Mean decreases were more evident for VAT [−3.55 (−4.94; −2.17) cm²] and steatosis [L/S ratio increase +0.17 (+0.13; +0.20)] than for TAT. In multivariable models adjusted by age, sex, and baseline TAT, increasing the CRP interval was associated with greater PMA reductions, smaller PMD increases, and greater VAT and steatosis decreases, but it was not associated with TAT decreases. In conclusion, muscle loss and fat loss (more apparent in visceral compartments) continue until 6–7 months after COVID-19. The inflammatory burden is associated with skeletal muscle loss and visceral/liver fat loss.