The role of immunotherapy in microsatellites stable metastatic colorectal cancer: state of the art and future perspectives

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, despite several advances has been achieved in last decades. Few prognostic and predictive biomarkers guide therapeutic choice in metastatic CRC (mCRC), among which DNA mismatch repair deficiency and/or microsatellite instability (dMMR/MSI) holds a crucial role. Tumors characterized by dMMR/MSI benefit from immune checkpoint inhibitors. However, most of the mCRC patients (around 95%) are microsatellite stable (MSS), thereby intrinsically resistant to immunotherapy. This represents a clear unmet need for more effective treatments in this population of patients. In this review, we aim to analyze immune-resistance mechanisms and therapeutic strategies to overcome them, such as combinations of immunotherapy and chemotherapy, radiotherapy or target therapies specifically in MSS mCRC. We also explored both available and potential biomarkers that may better select MSS mCRC patients for immunotherapy. Lastly, we provide a brief overview on future perspectives in this field, such as the gut microbiome and its potential role as immunomodulator

Distinct Patterns of DNA Damage Response and Apoptosis Correlate with Jak/Stat and PI3Kinase Response Profiles in Human Acute Myelogenous Leukemia

BACKGROUND:Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in intracellular signaling responses. Here SCNP was used to characterize Acute Myeloid Leukemia (AML) disease subtypes based on survival, DNA damage response and apoptosis pathways. METHODOLOGY AND PRINCIPAL FINDINGS:Thirty four diagnostic non-M3 AML samples from patients with known clinical outcome were treated with a panel of myeloid growth factors and cytokines, as well as with apoptosis-inducing agents. Analysis of induced Jak/Stat and PI3K pathway responses in blasts from individual patient samples identified subgroups with distinct signaling profiles that were not seen in the absence of a modulator. In vitro exposure of patient samples to etoposide, a DNA damaging agent, revealed three distinct "DNA damage response (DDR)/apoptosis" profiles: 1) AML blasts with a defective DDR and failure to undergo apoptosis; 2) AML blasts with proficient DDR and failure to undergo apoptosis; 3) AML blasts with proficiency in both DDR and apoptosis pathways. Notably, AML samples from clinical responders fell within the "DDR/apoptosis" proficient profile and, as well, had low PI3K and Jak/Stat signaling responses. In contrast, samples from clinical non responders had variable signaling profiles often with in vitro apoptotic failure and elevated PI3K pathway activity. Individual patient samples often harbored multiple, distinct, leukemia-associated cell populations identifiable by their surface marker expression, functional performance of signaling pathway in the face of cytokine or growth factor stimulation, as well as their response to apoptosis-inducing agents. CONCLUSIONS AND SIGNIFICANCE:Characterizing and tracking changes in intracellular pathway profiles in cell subpopulations both at baseline and under therapeutic pressure will likely have important clinical applications, potentially informing the selection of beneficial targeted agents, used either alone or in combination with chemotherapy

Development of RAPD-AFLP map of eggplant and improvement of tolerance to Verticillium wilt

Verticillium wilt is one of the most serious diseases in eggplant and one of the main goals of eggplant breeding is the achievement of Verticillium wilt tolerant hybrids. Solanum sodomeum L. has shown a mechanism of partial resistance against Verticillium wilt. Interspecific hybrids were obtained by using an accession of S. sodomeum from Sicily and the eggplant variety Buia. The results of the screenings for eggplant genotypes tolerant/resistant to Verticillium wilt by using backcrosses are reported. In a naturally infected field, from 1998 to 2001, the resistance to V dahliae of backcrossed progenies was increased by about 60%. The interspecific hybrids were both selfed and backcrossed using different types of eggplant. An integrated linkage map of eggplant (Solanum melongena L.) has been obtained by using 48 plants of an F-2 population. Starting from a genetic RAPDs map with similar to 100 markers mapped on 13 linkage groups, 4 AFLPs primer combinations were screened in order to improve the genetic map with the aim to achieve markers linked to Verticillium tolerance. Mendelian segregation of loci was verified by chi-square tests of the expected 3:1 and 1:1 ratios. Marker order was determined and all the data were combined to construct the most likely map. The integrated analysis of markers resulted in the construction of a map consisting of 273 loci and 12/13 linkage groups spanning 736 cM in a total. Linkage between different AFLP markers and the tolerance to Verticillium is discussed

Genetic improvement of eggplant for resistance to Verticillium through intersfecific hybridization with Solanum sodomeum. ".

Special Issue Capsicum News p.p

Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer

Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15–20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors

Assessing the Impact of the COVID-19 Outbreak on the Attitudes and Practice of Italian Oncologists Toward Breast Cancer Care and Related Research Activities

To investigate the impact of the COVID-19 outbreak on the attitudes and practice of Italian oncologists toward breast cancer care and related research activities

Criteri di appropriatezza clinica, tecnologica e strumentale nell'assistenza alle malattie del sistema cardiovascolare

Documento scientifico di indirizzo elaborato da un comistato ristretto di esperti del Ministero della Salute, relativo alla prevenzione diagnosi terapia e riabilitazione delle malattie del sistema cardio- cerebrovascolare e vascolari periferich

Beyond First-Line Immunotherapy: Potential Therapeutic Strategies Based on Different Pattern Progressions: Oligo and Systemic Progression

First-line immune-checkpoint inhibitor (ICI)-based therapy has deeply changed the treatment landscape and prognosis in advanced non-small cell lung cancer (aNSCLC) patients with no targetable alterations. Nonetheless, a percentage of patients progressed on ICI as monotherapy or combinations. Open questions remain on patients’ selection, the identification of biomarkers of primary resistance to immunotherapy and the treatment strategies to overcome secondary resistance to first-line immunotherapy. Local ablative approaches are the main therapeutic strategies in oligoprogressive disease, and their role is emerging in patients treated with immunotherapy. Many therapeutic strategies can be adapted in aNSCLC patients with systemic progression to personalize the treatment approach according to re-characterization of the tumors, previous ICI response, and type of progression. This review’s aim is to highlight and discuss the current and potential therapeutic approaches beyond first-line ICI-based therapy in aNSCLC patients based on the pattern of disease progression (oligoprogression versus systemic progression)