Paradoxical control of multifocal mammary oncogenesis by radiation therapy.

In an immunocompetent mouse model of multifocal, metachronous HR mammary carcinogenesis, we have recently demonstrated that a superior control of primary neoplastic lesions by focal radiotherapy does not necessarily translate into improved oncosuppression at non-irradiated (pre)malignant tissues. These data point to a link between local tumor control by radiotherapy and systemic oncogenesis that remains to be fully understood.

Targeting CDK2 to circumvent treatment resistance in HR breast cancer.

Genetic and epigenetic defects of the p53 system have previously been associated with resistance to CDK4/6 inhibitors in women with HR breast cancer. Recent data from Kudo et al. demonstrate that CDK2-targeting agents may offer an effective strategy to circumvent such resistance by enforcing cellular senescence downstream of RBL2 dephosphorylation.

Prognostic value of atypical B cells in breast cancer.

The impact of tumor-infiltrating B cells on breast cancer (BRCA) outcomes remains poorly understood. Recent findings from Yang et al. identify an atypical, clonally expanded population of activated Fc receptor-like 4 (FCRL4) B cells that is associated with improved overall survival in patients affected by various tumor types, including BRCA.

Recent advances and prospects of constructed wetlands in cold climates: a review from 2013 to 2023.

Constructed wetland (CW), a promising, environmentally responsible, and effective green ecological treatment technology, is actively involved in the treatment of various forms of wastewater. Low temperatures will, however, lead to issues including plant dormancy, decreased microbial activity, and ice formation in CWs, which will influence how well CWs process wastewater. Applying CWs successfully and continuously in cold areas is extremely difficult.

Impact of COVID-19 on ophthalmic surgical procedures in sub-Saharan Africa: a multicentre study.

Background: The COVID-19 pandemic had a profound impact on healthcare and ophthalmology services globally. Numerous studies amongst various medical and surgical specialties showed a reduction in patient attendance and surgical procedures performed. Prior published ophthalmic literature focused on specific types of procedures and were usually single centre.

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.

Lessons for the Next Generation of Scientists from the Second Annual Arthur and Sandra Irving Cancer Immunology Symposium.

The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to success, the senior faculty mentors provide an invaluable resource to support the development of the next generation of leaders in the cancer immunology community. This Commentary describes some of the key topics that were discussed during the 2022 symposium: scientific and career trajectory, leadership, mentoring, collaborations, and publishing.

Leveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies.

Anticancer immunotherapies, such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells, have improved outcomes for patients with a variety of malignancies. However, most patients either do not initially respond or do not exhibit durable responses due to primary or adaptive/acquired immune resistance mechanisms of the tumor microenvironment. These suppressive programs are myriad, different between patients with ostensibly the same cancer type, and can harness multiple cell types to reinforce their stability.

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.

Quantitative assessment of mitophagy in irradiated cancer cells.

Mitophagy is a finely regulated mechanism through which eukaryotic cells selectively dispose of supernumerary, permeabilized or otherwise damaged mitochondria through lysosomal degradation. Dysfunctional mitochondria are prone to release potentially cytotoxic factors including reactive oxygen species (ROS) and caspase activators, such as cytochrome c, somatic (CYCS). Thus, proficient mitophagic responses mediate prominent cytoprotective functions.

Cytofluorometric assessment of acute cell death responses driven by radiation therapy.

Radiation therapy (RT) is well known for its capacity to mediate cytostatic and cytotoxic effects on malignant cells, largely reflecting the ability of ionizing radiation to cause direct and indirect damage to macromolecules including DNA and lipids. While low-dose RT generally causes limited cytotoxicity in an acute manner (as it imposes insufficient cellular damage to compromise homeostasis, or instead induces the delayed demise of cells that fail to complete mitosis successfully), high RT doses can mediate an acute wave of cell death that begins to manifest shortly (24-72h) after irradiation. Here, we provide two straightforward techniques to assess the acute cytotoxic effects of RT by the flow cytometry-assisted quantification of plasma membrane permeabilization (PMP, a late-stage manifestation of cell death) and either mitochondrial outer membrane permeabilization (MOMP) or phosphatidylserine (PS) externalization (two early-stage signs of cell death) in mouse mammary adenocarcinoma TS/A cells.

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.

PDIA3 epitope-driven immune autoreactivity contributes to hepatic damage in type 2 diabetes.

A diet rich in saturated fat and carbohydrates causes low-grade chronic inflammation in several organs, including the liver, ultimately driving nonalcoholic steatohepatitis. In this setting, environment-driven lipotoxicity and glucotoxicity induce liver damage, which promotes dendritic cell activation and generates a major histocompatibility complex class II (MHC-II) immunopeptidome enriched with peptides derived from proteins involved in cellular metabolism, oxidative phosphorylation, and the stress responses. Here, we demonstrated that lipotoxicity and glucotoxicity, as driven by a high-fat and high-fructose (HFHF) diet, promoted MHC-II presentation of nested T and B cell epitopes from protein disulfide isomerase family A member 3 (PDIA3), which is involved in immunogenic cell death.

Online Faculty Development: An African Lusophone Ophthalmic Society Experience During the COVID-19 Pandemic.

Purpose: Faculty development for procedural specialists aims at developing both their medical education and surgical competence. This has been challenging during the COVID-19 pandemic, especially in under-resourced settings and African Lusophone ophthalmology community has been no exception. The Mozambican College of Ophthalmology (MOC) and the Continuing Professional Development Committee of the International Council of Ophthalmology (ICO) established a collaboration to enhance simulation-based clinical teaching competence in cataract surgery.

Nicotinamide drives T cell activation in the mammary tumor microenvironment.

Nicotinamide (NAM, a variant of vitamin B) has recently been shown to accelerate the activation of human CD4 and CD8 T cells exposed to repeated CD3/CD28 agonism in vitro. Here, we demonstrate that T cells infiltrating mouse mammary carcinomas that are therapeutically controlled by NAM also express multiple markers of late-stage activation. Taken together, these findings lend additional support to the notion that the antineoplastic effects of NAM involve at least some degree of restored cancer immunosurveillance.

Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment.

Immune checkpoint inhibitors (ICIs) have revolutionized the clinical management of multiple tumours. However, only a few patients respond to ICIs, which has generated considerable interest in the identification of resistance mechanisms. One such mechanism reflects the ability of various oncogenic pathways, as well as stress response pathways required for the survival of transformed cells (a situation commonly referred to as 'non-oncogene addiction'), to support tumour progression not only by providing malignant cells with survival and/or proliferation advantages, but also by establishing immunologically 'cold' tumour microenvironments (TMEs).

LTX-315-enabled, radiotherapy-boosted immunotherapeutic control of breast cancer by NK cells.

LTX-315 is a nonameric oncolytic peptide in early clinical development for the treatment of solid malignancies. Preclinical and clinical evidence indicates that the anticancer properties of LTX-315 originate not only from its ability to selectively kill cancer cells, but also from its capacity to promote tumor-targeting immune responses. Here, we investigated the therapeutic activity and immunological correlates of intratumoral LTX-315 administration in three syngeneic mouse models of breast carcinoma, with a focus on the identification of possible combinatorial partners.