Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies

ERBB4 is a tyrosine kinase receptor reported to exert both oncogenic and tumor suppressor activities. These paradoxical effects were suggested to stem from different ERBB4 homo-/hetero-dimers and/or isoforms. By stratifying breast cancer patients for clinical and molecular subtypes and ERBB4 mRNA abundance, we here report that higher ERBB4 levels correlate with longer relapse-free survival in breast cancer patients of HER2-enriched and luminal A molecular subtypes, proposing a cancer-protecting role for this receptor in these specific subgroups. We also observed that HER2-enriched breast cancers express intermediate ERBB4 mRNA levels compared to luminal and triple-negative/basal-like subgroups, which displayed the highest and the lowest levels, respectively. Inspired by these clinical data, we tested the activation of ERBB4 by Neuregulins as a potential anticancer strategy for HER2+ breast cancers. To this end, we employed two HER2+ breast cancer cellular models (BT474 and SKBR3), which express intermediate/high and low ERBB4 levels, respectively. Cell proliferation and motility were evaluated on these cellular models following treatments with Neuregulin 1 (NRG1), which activates both ERBB3 and ERBB4, or Neuregulin 4 (NRG4), which specifically activates ERBB4. Both NRG1 and NRG4 were used alone or in combination with anti-ERBB2 neutralizing antibodies, namely trastuzumab and pertuzumab. In vitro treatment with NRG1 on BT474 cells restrained cell growth and reduced the anti-proliferative efficacy of trastuzumab. In contrast, treatment with NRG1 on SKBR3 cells increased cell proliferation and migration, and partially or completely impaired the anti-proliferative/anti-migratory action of trastuzumab and/or pertuzumab. Importantly, in both the cell lines, treatment with NRG4 robustly potentiated the anti-proliferative action of trastuzumab and pertuzumab. Collectively, our data in HER2+ breast cancer cells highlight that NRG1 may exert both pro- and anti-proliferative effects, and may reduce the efficacy of anti-HER2 agents, whereas NRG4 may boost the anti-proliferative effects of anti-ERBB2 agents. We propose a provocative paradigm shift in the field of growth factors in cancer progression, suggesting the administration of ERBB4 ligands, such as Neuregulin 4, as a strategy to improve the efficacy of anti-ERBB2 agents

A novel role for the interleukin-1 receptor axis in resistance to anti-EGFR therapy

Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy

Factors related to women’s psychological distress during the covid-19 pandemic: Evidence from a two-wave longitudinal study

Background. A growing body of research has highlighted the negative effects of the COVID-19 pandemic on women’s mental health. Previous studies showed that women have higher levels of depression, anxiety and PTSD, and worse psychological adjustment than men, which also persisted after the earlier phase of the pandemic. This study aimed to evaluate changes in women’s psychological distress during the pandemic and to evaluate the factors that have a more significant impact in predicting women’s psychological distress. Methods. This two-wave longitudinal study (T1 = Italian first lockdown, and T2 = second phase, when the restrictive measures were eased) involved 893 women (Mage = 36.45, SD = 14.48). Participants provided demographic and health data as well as measures of psychological distress, emotion regulation processes, and ability to tolerate uncertainty. Results. No significant changes were found in women’s psychological distress between T1 and T2, i.e., during and after the first lockdown. Lower social stability status and higher maladaptive emotional coping predicted high psychological distress. Conclusions. Results showed that modifiable psychological variables play a central role in predicting distress and indicated that emotion regulation interventions might be helpful in increasing psychological resilience and mitigating the adverse impacts of the COVID-19 pandemic within the female population

Extreme and long-term drought in the La Plata Basin: event evolution and impact assessment until September 2022

The current drought conditions across the Parana-La Plata Basin (LPB) in Brazil-Argentina have been the worst since 1944. While this area is characterized by a rainy season with a peak from October to April, the hydrological year 2020-2021 was very deficient in rainfall, and the situation extended into the 2021-2022 hydrological year. Below-normal rainfall was dominant in south-eastern Brazil, northern Argentina, Paraguay, and Uruguay, suggesting a late onset and weaker South American Monsoon and the continuation of drier conditions since 2021. In fact, in 2021 Brazilian south and south-east regions faced their worst droughts in nine decades, raising the spectre of possible power rationing given the grid dependence on hydroelectric plants. The Paraná-La Plata Basin drought induced damages to agriculture and reduced crop production, including soybeans and maize, with effects on global crop markets. The drought situation continued in 2022 in the Pantanal region. Dry meteorological conditions are still present in the region at the end of September 2022 with below-average precipitation anomalies. Soil moisture anomaly and vegetation conditions are worst in the lower part of the La Plata Basin, in the southern regions. Conversely, upper and central part of the basin show partial and temporary recovery

Parent Styles in Prospective Fathers: A Research Carried Out Using a Semistructured Interview During Pregnancy

Recent reviews on research into fathers consistently have drawn attention to the increased knowledge and thinking of the multifaceted, complex, and changing nature of fathers\u2019 role. Paternal involvement has been studied with reference to a number of variables, including personality, attitudes, and family structure. The concept of \u201cunderstanding mental states\u201d and of mentalization and the notion and working definition of Reflective Self Function, as devised by Fonagy and colleagues, seem to have important implications for paternal and parental involvement, and for normal development of the infant\u2013 caretaker relationship. The aim of our research was to broaden current knowledge and thinking about fathering during pregnancy by investigating how 112 prospective fathers are involved in the transition to fatherhood and how they are able to reflect on their experience. Our aim was to identify parental styles according to May\u2019s concepts and to rate Reflective Self Function in The Clinical Interview for Parents During Pregnancy [Colloquio per Genitori in Gravidanza (CGG)]. The CGG is a semistructured clinical interview devised with the most recent psychoanalytic views on mental representations taken into account and is aimed at investigating feelings and attitudes toward the baby, the couple\u2019s inner and subjective world. Our results highlighted the complexity of paternal involvement in pregnancy and its relation with Reflective Self Function. Specific relations also were found between Reflective Self Function and the three styles of detachment/involvement identified by Ma

Constructing the sense of self in psychosis using the amniotic therapy: a single case study

Some people diagnosed with “schizophrenia” showed a fundamental alteration of the sense of self. From a psychodynamic perspective, it has been hypothesized that patients diagnosed as schizophrenic have disorders of the embodied self and its boundaries. Phenomenologically, it has been observed a self-disorder, at an implicit and pre-reflective level of bodily awareness. Neuroscientific evidence seems to confirm the aforementioned aspects. The mean levels of Interoceptive Accuracy (IA), which is an objective empirical measure of interoception, namely a measure of basic awareness distinct from subjective measures, are significantly lower in patients with a diagnosis of schizophrenia than among healthy controls. Affiliative touch is crucial for constructing a basic sense of self and its boundaries, and it affects interoception. In order to reduce the disturbance of the sense of self, Angelo participated for three years in an experimental intervention plan including Amniotic Therapy (AT) and individual psychodynamic psychotherapy. AT is a group-therapy based on sensory-motor interactions, especially affiliative touch, similar to those involved in “holding”. Results showed an increase in the Angelo’s IA and global functioning, as well as a significant decrease in positive symptoms. In Angelo, AT seems to strengthen a basic sense of self, reducing self-disorder

A rock church preventive conservation project: the case study of the Crypt of one hundred Saints in Matera

The church of the Hundred Saints, now better known as the Crypt of the Original Sin, is located in the gorge “Gravina di Picciano”, about ten kilometers from Matera. The rock church and its decorations, dated back to the ninth century, were in critical condition when it was discovered and later acquired by the Zetema Foundation of Matera. In 2000, a monitoring project was started under the scientific direction of Michele D'Elia, and is still ongoing in collaboration with specialists from the ICR (now ISCR), from UniromaTre, and various technical experts. The project aimed to design a conservation plan and to find solutions not only for the specific problems, but also to develop a protocol for the conservation and maintenance of similar rock-art sites. The wall paintings were colonized by different microorganisms and showed problems of salt efflorescence and carbonatation. A program was set up to control bio-growth, carry out characterization of materials, test treatment products and perform interventions to resolve the site’s conservation problems. After concluding conservation treatment in 2004, two check-up and maintenance interventions followed in 2010 and 2017. These involved evaluating new degradation phenomena, the efficacy of biocidal products, the new cleaning method and the validity of the treatment choices adopted

The Codevelopment of Group Relationships: The Role of Individual Group Member's and Other Group Members' Mutual Influence and Shared Group Environment

Although recent research has provided empirical support for the codevelopment of group interaction (defined as development in a common direction of perceptions of group relationships), no studies have yet investigated the "causes" of codevelopment among group members in the long term. The aim of the current study is to examine how the perceptions of an individual group member, and other group members, regarding group relationships influence each other over the course of treatment. We analyzed group data from 168 adult obese patients who participated in (1 of 20) 12-session therapy groups for weight management. Group relationships were measured by the Group Questionnaire (Krogel et al., 2013), which was administered to group members in early, middle and late group sessions. The longitudinal version of the group actor-partner interdependence model was used to analyze the influence among members. Results showed that there is no mutual influence in the codevelopment of both positive bonding and negative relationship. However, positive bonding of other group members in the middle of the group influenced positive bonding of the individual group member in the late group session. Moreover, individual group member negative relationships in early and middle sessions influenced other group member negative relationships in middle and late sessions. Finally, there was evidence of mutual influence in the codevelopment of positive working early in the group. The findings show that the process of influence among members is complex with regard to the specific dimension of the group relationship assessed and the time spent in group treatment