Therapeutic potential of co-signaling receptor modulation in hepatitis B.

Reversing CD8 T cell dysfunction is crucial in treating chronic hepatitis B virus (HBV) infection, yet specific molecular targets remain unclear. Our study analyzed co-signaling receptors during hepatocellular priming and traced the trajectory and fate of dysfunctional HBV-specific CD8 T cells. Early on, these cells upregulate PD-1, CTLA-4, LAG-3, OX40, 4-1BB, and ICOS.

Preclinical evaluation of therapeutic vaccines for chronic hepatitis B that stimulate antiviral activities of T cells and NKT cells.

Background & Aims: Liver diseases resulting from chronic HBV infection are a significant cause of morbidity and mortality. Vaccines that elicit T-cell responses capable of controlling the virus represent a treatment strategy with potential for long-term effects. Here, we evaluated vaccines that induce the activity of type I natural killer T (NKT) cells to limit viral replication and license stimulation of conventional antiviral T-cells.

Antibody-independent protection against heterologous SARS-CoV-2 challenge conferred by prior infection or vaccination.

Vaccines have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) morbidity and mortality, yet emerging variants challenge their effectiveness. The prevailing approach to updating vaccines targets the antibody response, operating under the presumption that it is the primary defense mechanism following vaccination or infection. This perspective, however, can overlook the role of T cells, particularly when antibody levels are low or absent.

CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus.

CD8 T cells are key antiviral effectors against hepatitis B virus (HBV), yet their number and function can be compromised in chronic infections. Preclinical HBV models displaying CD8 T cell dysfunction showed that interleukin-2 (IL-2)-based treatment, unlike programmed cell death ligand 1 (PD-L1) checkpoint blockade, could reverse this defect, suggesting its therapeutic potential against HBV. However, IL-2's effectiveness is hindered by its pleiotropic nature, because its receptor is found on various immune cells, including regulatory T (T) cells and natural killer (NK) cells, which can counteract antiviral responses or contribute to toxicity, respectively.

Discovery and antiviral profile of new sulfamoylbenzamide derivatives as HBV capsid assembly modulators.

Chronic hepatitis B (CHB) is a major worldwide public health problem and novel anti-HBV therapies preventing liver disease progression to cirrhosis and hepatocellular carcinoma are urgently needed. Over the last several years, capsid assembly modulators (CAM) have emerged as clinically effective anti-HBV agents which can inhibit HBV replication in CHB patients. As part of a drug discovery program aimed at obtaining novel CAM endowed with high in vitro and in vivo antiviral activity, we identified a novel series of sulfamoylbenzamide (SBA) derivatives.

Group 1 ILCs regulate T cell-mediated liver immunopathology by controlling local IL-2 availability.

Group 1 innate lymphoid cells (ILCs), which comprise both natural killer (NK) cells and ILC1s, are important innate effectors that can also positively and negatively influence adaptive immune responses. The latter function is generally ascribed to the ability of NK cells to recognize and kill activated T cells. Here, we used multiphoton intravital microscopy in mouse models of hepatitis B to study the intrahepatic behavior of group 1 ILCs and their cross-talk with hepatitis B virus (HBV)-specific CD8 T cells.

Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion.

The development of a tractable small animal model faithfully reproducing human coronavirus disease 2019 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high central nervous system infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model’s usefulness.

COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models.

The COVID-19 pandemic caused by SARS-CoV-2 has made the development of safe and effective vaccines a critical priority. To date, four vaccines have been approved by European and American authorities for preventing COVID-19, but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle.

Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming.

Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages known for their scavenger and phagocytic functions. KCs can also present antigens to CD8 T cells and promote either tolerance or effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) infection, in which HBV-specific naive CD8 T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction, to identify a subset of KCs (referred to as KC2) that cross-presents hepatocellular antigens upon interleukin-2 (IL-2) administration, thus improving the antiviral function of T cells.

Spatiotemporal regulation of type I interferon expression determines the antiviral polarization of CD4 T cells.

Differentiation of CD4 T cells into either follicular helper T (T) or type 1 helper T (T1) cells influences the balance between humoral and cellular adaptive immunity, but the mechanisms whereby pathogens elicit distinct effector cells are incompletely understood. Here we analyzed the spatiotemporal dynamics of CD4 T cells during infection with recombinant vesicular stomatitis virus (VSV), which induces early, potent neutralizing antibodies, or recombinant lymphocytic choriomeningitis virus (LCMV), which induces a vigorous cellular response but inefficient neutralizing antibodies, expressing the same T cell epitope. Early exposure of dendritic cells to type I interferon (IFN), which occurred during infection with VSV, induced production of the cytokine IL-6 and drove T cell polarization, whereas late exposure to type I IFN, which occurred during infection with LCMV, did not induce IL-6 and allowed differentiation into T1 cells.

Use of nivolumab in elderly patients with advanced squamous non-small-cell lung cancer: results from the Italian cohort of an expanded access programme.

Aim: This analysis evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, in elderly patients with stage IIIB or IV squamous non-small-cell lung cancer (NSCLC) enrolled in the expanded access programme (EAP) in Italy.

Methods: Nivolumab was available on physician request. Safety data included adverse events (AEs).

Efficacy and safety data in elderly patients with metastatic renal cell carcinoma included in the nivolumab Expanded Access Program (EAP) in Italy.

Background: Results from phase III clinical trial CheckMate 025 have established nivolumab as the standard of care for treatment of metastatic renal-cell carcinoma (mRCC) after VEGF inhibitor failure; however, elderly patients are under-represented in the registration trial and little is known about the activity of nivolumab in this subgroup. The purpose of the Expanded Access Program was to provide nivolumab to patients with mRCC who had progressed despite treatment with other agents that were considered standard of care.

Methods: Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months or until progression or unacceptable toxicity.

Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors.

The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48).

A SCARECROW-based regulatory circuit controls Arabidopsis thaliana meristem size from the root endodermis.

SCARECROW controls Arabidopsis root meristem size from the root endodermis tissue by regulating the DELLA protein RGA that in turn mediates the regulation of ARR1 levels at the transition zone. Coherent organ growth requires a fine balance between cell division and cell differentiation. Intriguingly, plants continuously develop organs post-embryonically thanks to the activity of meristems that allow growth and environmental plasticity.

Adult primary paratesticular mesenchymal tumors with emphasis on a case presentation and discussion of spermatic cord leiomyosarcoma.

Background: The aim of this report is related to adult primary paratesticular mesenchymal tumors with emphasis on a case presentation and discussion of the spermatic cord leiomyosarcoma. Primary paratesticular tumors are rare, only accounting for 7% to 10% of all intrascrotal tumors. In adults, more than 75% of these lesions arise from the spermatic cord, 20% being leiomyosarcoma.

Medical oncologist's commitment in end-of-life care of cancer patients.

Objective: Cancer patients and family members can feel abandoned by their oncologist at the transition to end-of-life (eoL) care. In this study, we evaluated the level of satisfaction of family caregivers when the oncology team assisted the patient until death.

Methods: Two oncology units were reorganized to ensure continuity of care; oncologists trained in palliative care medicine assisted patients until death.

Spatiotemporal changes in the role of cytokinin during root development.

The root is a dynamic system whose structure is regulated by a complex network of interactions between hormones. The primary root meristem is specified in the embryo. After germination, the primary root meristem grows and then reaches a final size that will be maintained during the life of the plant.

Impact of use of oral anticancer drugs on activity of Italian oncology practices: results of a survey conducted by the Italian Society of Medical Oncology (AIOM).

Aims And Background: In recent years, the number of oral anticancer drugs used in clinical practice has rapidly increased. The Italian Society of Medical Oncology (AIOM) conducted a survey to describe the impact of the use of oral anticancer drugs on the daily activity of Italian oncology practices.

Methods And Study Design: A survey questionnaire was distributed to the coordinators of the regional sections of AIOM.

A phase II study of modified FOLFOX as first-line chemotherapy for metastatic gastric cancer in elderly patients with associated diseases.

Background: Elderly patients are generally underrepresented in the study populations of combination chemotherapy trials. This study evaluates the efficacy and safety of a modified FOLFOX regimen in elderly patients with metastatic gastric cancer and presenting associated disease(s).

Methods: A total of 43 patients aged ≥70 years received oxaliplatin 85 mg/m(2) together with 6S-leucovorin 200 mg/m(2) on day 1, followed by a 46-h infusion of 5-fluorouracil 2,400 mg/m(2), every 2 weeks.

Phosphorylated AKT and MAPK expression in primary tumours and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab.

Background: Clinical observations suggested that a non negligible proportion of patients, ranging from 40% to 70%, does not seem to benefit from the use of anti-EGFR targeted antibodies even in the absence of a mutation of the K- RAS gene. The EGFR pathway activation via the Ras-Raf-MAP-kinase and the protein-serine/threonine kinase AKT could determine resistance to anti-EGFR treatment.

Methods: We tested the interaction between phosphorylated AKT and MAPK expression in colorectal tumours and corresponding metastases and global outcome in K-RAS wild type patients receiving irinotecan-cetuximab.

Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab.

Background: A large proportion of colorectal cancer patients does not benefit from the use of anti-epidermal growth factor receptor (EGFR) treatment although in the absence of a mutation of the K-RAS gene. Preliminary observations suggested that HER-3, insulin-like growth factor-1 (IGF-1), nuclear factor-kB (NF-kB) and EGFR gene copy number (GCN) might identify patients not likely to benefit from anti-EGFR therapy. We tested the interaction between HER-3, IGF-1, NF-kB, EGFR GCN and K-RAS mutational analysis to verify the relative ability of these variables to identify a subgroup of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild-type status.

Disparity in the "time to patient access" to new anti-cancer drugs in Italian regions. Results of a survey conducted by the Italian Society of Medical Oncology (AIOM).

Aims And Background: In 2009, the Italian Society of Medical Oncology (AIOM) conducted a survey to describe the impact of regional pharmaceutical formularies on the disparity of access to eight new drugs among cancer patients treated in Italian regions. The survey documented some regional restrictions for some anti-cancer drugs. In the study, we analyzed the "time to patient access" to new anti-cancer drugs in Italian regions.

Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer.

Background: Previous studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer.

Patients And Methods: This study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments.

Differences in the availability of new anti-cancer drugs for Italian patients treated in different regions. Results of analysis conducted by the Italian Society Of Medical Oncology (AIOM).

Aims And Background: Italy is divided into 20 regions. As a consequence of local autonomy, following marketing authorization by the Italian Medicines Agency, each drug for hospital use is not immediately available, because its approval needs to undergo further steps that can be different among regions. The Italian Society of Medical Oncology conducted the present study to describe the impact of the existence of sub-national pharmaceutical formularies on the disparity of access to new anti-cancer drugs among patients treated in different Italian regions.