An immunological mechanism of resistance to CDK4/6 inhibitors in HR breast cancer.

CDK4/6 inhibitors are central to the clinical management of HRHER2 breast cancer. We have recently demonstrated that immunosuppressive, IL17-secreting γδ T cells recruited to the tumor microenvironment by a CCL2-dependent mechanism upon CDK4/6 inhibition can repolarize tumor-associated macrophages toward a CX3CR1 phenotype associated with resistance to therapy.

IL-17A-secreting γδ T cells promote resistance to CDK4/CDK6 inhibitors in HRHER2 breast cancer via CX3CR1 macrophages.

Resistance to cyclin-dependent kinase 4/6 (CDK4/CDK6) inhibitors leads to treatment failure and disease progression in women with hormone receptorHER2 (HRHER2) breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting interleukin-17A (IL-17A)-secreting γδ T cells to mouse HRHER2 BCs following CDK4/CDK6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) toward an immunosuppressive CX3CR1 phenotype associated with resistance. Increased IL-17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of individuals with HRHER2 BC.

A case study of forensic psychiatry experts' reports analysis through large language models.

The integration of artificial intelligence (AI) technologies in forensic psychiatry has gained significant attention due to their potential to enhance tasks such as outcome prediction and decision-making. In this study, we explored the feasibility and performance of a large language model (LLM-GPT) in extracting both clinical and non-clinical variables from authentic forensic psychiatric reports concerning defendants' criminal responsibility and social dangerousness. We employed GPT-4o to extract relevant data using a set of custom queries, which we applied to two forensic psychiatric expert reports.

CYPD limits HR mammary carcinogenesis in mice.

Mitochondrial permeability transition (MPT)-driven necrosis and necroptosis are regulated variants of cell death that can drive inflammation or even promote antigen-specific immune responses. In oncological settings, indolent inflammatory reactions have been consistently associated with accelerated disease progression and resistance to treatment. Conversely, adaptive immune responses specific for tumor-associated antigens are generally restraining tumor development and contribute to treatment sensitivity.

Histological Analysis of Biological Width and Collagen Fibers Orientation Around Screw-Less, Morse Taper, Hemispherical Base Abutments 8 and 16 Weeks After Implant Uncovering: An Observational Clinical Trial.

This study aimed to histologically evaluate, in humans, the orientation of collagen fibers around screw-less, Morse taper, hemispherical base abutments. This study was designed as an observational, case-control, clinical trial to evaluate the histological orientation of collagen fibers around implants. Biopsies of the peri-implant tissue were performed 8 (group A, control) or 16 (group B, test) weeks of implant uncovering, and histologically analyzed under optical microscope using Hematoxylin and Eosin, Masson, and Picro Sirius histochemical staining and a scanning electron microscope.

Clinical and legal issues of inmates' food refusal: the importance of decision-making capacity assessment.

Inmates' food refusal is a large-scale phenomenon raising clinical, ethical, and professional responsibility issues. Obtaining a clinical balance of the right to refuse food with the right to protect the inmate's health can be a challenging process. Several reasons may support inmates' choice of refusing food, including political or protest reasons, as well as psychiatric disorders.

Exceptional bone remodeling over composite restoration in the management of external root resorption: A case report.

A 65-year-old Caucasian male was referred to an endodontic specialist practice in a private clinic in December 2019 for the management of an asymptomatic, radiolucent lesion located at the cervical level of the distal root of his right lower first molar, noticed during a routine periapical radiograph. After an accurate evaluation with cone-beam computed tomography (CBCT), the subgingival lesion was diagnosed as a supracrestal external cervical resorption (ECR), with a circumferential spread ⩽90°, confined to dentine without pulp involvement. The lesion was treated with the following sequence: (1) a full flap accessed the ECR, (2) the granulomatous tissue was removed from the root area, (3) the cavity was refreshed and filled with a well-refined and polished resin composite, (4) the flap was sutured at the cemento-enamel junction.

Exploiting Tertiary Lymphoid Structures to Stimulate Antitumor Immunity and Improve Immunotherapy Efficacy.

Tumor-associated tertiary lymphoid structures (TLS) have been associated with favorable clinical outcomes and response to immune checkpoint inhibitors in many cancer types, including non-small cell lung cancer. Although the detailed cellular and molecular mechanisms underlying these clinical associations have not been fully elucidated, growing preclinical and clinical studies are helping to elucidate the mechanisms at the basis of TLS formation, composition, and regulation of immune responses. However, a major challenge remains how to exploit TLS to enhance naïve and treatment-mediated antitumor immune responses.

Flow cytometry-assisted quantification of cell cycle arrest in cancer cells treated with CDK4/6 inhibitors.

Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (i.e., palbociclib, abemaciclib, and ribociclib) are well known for their capacity to mediate cytostatic effects by promoting cell cycle arrest in the G phase, thus inhibiting cancer cell proliferation.

Between psychopathy and deviant socialization: A close look at the mafia men.

The Italian mafia organizations represent a subculture with values, beliefs and goals that are antithetical to and undermining of the predominant society. The conduct of individual members includes such extreme violence for material gain, it may at least superficially suggest a severe personality disorder. Since the first edition of the DSM and into the 21st century, various terms have been used, sometimes interchangeably, but over time inconsistently, to designate the mentality and practices of mafia members.

Cellular senescence in the response of HR breast cancer to radiotherapy and CDK4/6 inhibitors.

Background: Preclinical evidence from us and others demonstrates that the anticancer effects of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can be enhanced with focal radiation therapy (RT), but only when RT is delivered prior to (rather than after) CDK4/6 inhibition. Depending on tumor model, cellular senescence (an irreversible proliferative arrest that is associated with the secretion of numerous bioactive factors) has been attributed beneficial or detrimental effects on response to treatment. As both RT and CDK4/6 inhibitors elicit cellular senescence, we hypothesized that a differential accumulation of senescent cells in the tumor microenvironment could explain such an observation, i.

Quantification of beta-galactosidase activity as a marker of radiation-driven cellular senescence.

Cellular senescence is a permanent state of cell cycle arrest that can be triggered by different stressors, including cancer treatments (the so-called "therapy-induced senescence"), such as radiation therapy (RT). Although senescent cells do not proliferate, they remain metabolically active and play a critical role in tumor progression, metastasis, and response to therapy. Therefore, investigating the induction of cellular senescence upon RT treatment is a critical read out for investigating RT efficacy or combinatorial strategies in cancer research.

Challenges in the treatment of small cell lung cancer in the era of immunotherapy and molecular classification.

For many years the standard of care for small cell lung cancer (SCLC) has remained unchanged. Despite decades of active research, current treatment options are limited and the prognosis of patients with extended disease (ED) SCLC remains poor. The introduction of immune checkpoint inhibitors (ICIs) represents an exception and the only recent approval for ED-SCLC.

Profiling Players Involved in Overkill: An Analysis of 71 Cases in Central Italy.

"Overkill" is characterized by the finding of excessive wounds on the victim's body. Despite the large use of this term, it does not have a definition in the literature yet. Our study aimed to analyze the information related to the dynamics of overkill cases, collecting objective variables, and producing a profile of the players involved in this type of homicides.

RT-PCR-assisted quantification of type I IFN responses in irradiated cancer cells.

It is now clear that radiation therapy (RT) can be delivered in doses and according to fractionation schedules that actively elicit immunostimulatory effects. While such effects are often sufficient to drive potent anticancer immunity culminating with systemic disease eradication, the immunostimulatory activity of RT stands out as a promising combinatorial partner for bona fide immunotherapeutics including immune checkpoint inhibitors (ICIs). Accumulating preclinical and clinical evidence indicates that the secretion of type I interferon (IFN) by irradiated cancer cells is a sine qua non for RT to initiate ICI-actionable tumor-targeting immune responses.

Quantification of cytosolic DNA species by immunofluorescence microscopy and automated image analysis.

When employed according to specific doses and fractionation schedules, radiation therapy (RT) elicits potent tumor-targeting immune responses that rely on the secretion of type I interferon (IFN) by irradiated cancer cells. Most often, this is initiated by the ability of RT to promote the cytosolic accumulation of double-stranded DNA (dsDNA) molecules, which are detected by cyclic GMP-AMP synthase (CGAS) to engage the stimulator of interferon response cGAMP interactor 1 (STING1)-dependent transactivation of type I IFN-coding genes via interferon regulatory factor 3 (IRF3). Here, we describe a simple protocol for the quantification of cytosolic dsDNA species by immunofluorescence microscopy coupled to automated image analysis, as enabled by precise sample processing conditions that permeabilize plasma-but not nuclear or inner mitochondrial-membranes.

Cytofluorometric assessment of cell cycle progression in irradiated cells.

Radiation therapy (RT) is well known for its capacity to mediate cytostatic and cytotoxic effects upon the accumulation of unrepaired damage to macromolecules, notably DNA. The ability of ionizing radiation to prevent malignant cells from replicating and to cause their demise is indeed an integral component of the anticancer activity of RT. Neoplastic cells are generally more sensitive to the cytostatic and cytotoxic effects of RT than their healthy counterparts as they exhibit increased proliferative rate and limited capacity for DNA repair.

A Rapid Fatal Outcome of Iliopsoas Hematoma: Clinical and Autopsy Findings.

A case of massive muscular bleeding of iliopsoas resulting in lethal exsanguination is presented. The intramuscular bleeding occurred spontaneously in an old man with heart failure, presented to the emergency department after the acute onset of shortness of breath, and treated with therapeutic doses of antiplatelets and heparin to prevent thrombosis. On the sixth day of recovery, pain in the left lumbar region develops while there was a decrease in hemoglobin level.