The immunology of Epstein-Barr virus-induced disease.

Epstein-Barr virus (EBV) is usually acquired silently early in life and carried thereafter as an asymptomatic infection of the B lymphoid system. However, many circumstances disturb the delicate EBV-host balance and cause the virus to display its pathogenic potential. Thus, primary infection in adolescence can manifest as infectious mononucleosis (IM), as a fatal illness that magnifies the immunopathology of IM in boys with the X-linked lymphoproliferative disease trait, and as a chronic active disease leading to life-threatening hemophagocytosis in rare cases of T or natural killer (NK) cell infection. Patients with primary immunodeficiencies affecting the NK and/or T cell systems, as well as immunosuppressed transplant recipients, handle EBV infections poorly, and many are at increased risk of virus-driven B-lymphoproliferative disease. By contrast, a range of other EBV-positive malignancies of lymphoid or epithelial origin arise in individuals with seemingly intact immune systems through mechanisms that remain to be understood.

Telomere-lengthening germline variants predispose to a syndromic papillary thyroid cancer subtype.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy. 10% to 15% of individuals show familial clustering with three or more affected members, but the factors underlying this risk are unknown. In a group of recently studied individuals with POT1 pathogenic variants and ultra-long telomere length, PTC was the second most common solid tumor. We tested whether variants in POT1 and four other telomere-maintenance genes associated with familial cancer underlie PTC susceptibility. Among 470 individuals, we identified pathogenic or likely pathogenic variants in three genes encoding telomere-binding proteins: POT1, TINF2, and ACD. They were found in 4.5% and 1.5% of familial and unselected cases, respectively. Individuals harboring these variants had ultra-long telomere length, and 15 of 18 (83%) developed other cancers, of which melanoma, lymphoma, and sarcoma were most common. Among individuals with PTC and melanoma, 22% carried a deleterious germline variant, suggesting that a long telomere syndrome might be clinically recognizable. Successive generations had longer telomere length than their parents and, at times, developed more cancers at younger ages. Tumor sequencing identified a single oncogenic driver, BRAF p.Val600Glu, in 10 of 10 tumors studied, but no telomere-maintenance mechanism, including at the TERT promoter. These data identify a syndromic subset of PTCs with locus heterogeneity and telomere lengthening as a convergent mechanism. They suggest these germline variants lower the threshold to cancer by obviating the need for an acquired telomere-maintenance mechanism in addition to sustaining the longevity of oncogenic mutations.

Inflammasomes as regulators of non-infectious disease.

Inflammasomes are cytoplasmic organelles that stimulate inflammation upon cellular detection of infectious or non-infectious stress. While much foundational work has focused on the infection-associated aspects of inflammasome activities, recent studies have highlighted the role of inflammasomes in non-infectious cellular and organismal functions. Herein, we discuss the evolution of inflammasome components and highlight characteristics that permit inflammasome regulation of physiologic processes. We focus on emerging data that highlight the importance of inflammasome proteins in the regulation of reproduction, development, and malignancy. A framework is proposed to contextualize these findings.

Tools to facilitate communication during physician-patient consultations in cancer care: An overview of systematic reviews.

Tools have been developed to facilitate communication and support information exchange between people diagnosed with cancer and their physicians. Patient-reported outcome measures, question prompt lists, patient-held records, tape recordings of consultations, decision aids, and survivorship care plans have all been promoted as potential tools, and there is extensive literature exploring their impact on patient outcomes. Eleven systematic reviews of studies evaluating tools to facilitate patient-physician communication were reviewed and summarized in this overview of systematic reviews. Across the systematic reviews, 87 publications reported on 84 primary studies involving 15,381 participants. Routine use of patient-reported outcome measures and feedback of results to clinicians can improve pain management, physician-patient communication, and symptom detection and control; increase utilization of supportive care; and increase patient involvement in care. Question prompt lists can increase the number of questions asked by patients without increasing consultation length and may encourage them to reflect and plan questions before the consultation. There is limited benefit in audio recording consultations or using patient-held records during consultations. Physicians should be supported by adequately resourced health services to respond effectively to the range of clinical and broader patient needs identified through the routine use of tools to facilitate communication.

Clonal Hematopoiesis and Its Impact on Human Health.

Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal expansion. This process occurs in several tissues but has been best studied in blood. Clonal hematopoiesis is associated with an increased risk of blood cancers, such as acute myeloid leukemia, which result if additional cooperating mutations occur. Surprisingly, it is also associated with an increased risk of nonmalignant diseases, such as atherosclerotic cardiovascular disease. This may be due to enhanced inflammation in mutated innate immune cells, which could be targeted clinically with anti-inflammatory drugs. Recent studies have uncovered other factors that predict poor outcomes in patients with clonal hematopoiesis, such as size of the mutant clone, mutated driver genes, and epigenetic aging. Though clonality is inevitable and largely a function of time, recent work has shown that inherited genetic variation can also influence this process. Clonal hematopoiesis provides a paradigm for understanding how age-related changes in tissue stem cell composition and function influence human health.

Therapeutic tactics for targeting B lymphocytes in autoimmunity and cancer.

B lymphocytes have become a very popular therapeutic target in a number of autoimmune indications due to their newly appreciated roles, and approachability, in these diseases. Many of the therapies now applied in autoimmunity were initially developed to deplete malignant B cells. These strategies have also been found to benefit patients suffering from such autoimmune diseases as multiple sclerosis, type I diabetes, systemic lupus erythematosus, and rheumatoid arthritis, to name a few. These observations have supported the expansion of research addressing the mechanistic contributions of B cells in these diseases, as well as blossoming of therapeutics that target them. This review seeks to summarize cutting-edge modalities for targeting B cells, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, chimeric antigen receptor-T cells, and small molecule inhibitors. Efforts to refine B-cell targeted therapy to eliminate only pathogenic autoreactive cells will be addressed as well as the potential for future B-cell-based cellular therapeutics. Finally, we also address approaches that seek to silence B-cell function without depletion.

Improving artificial intelligence pipeline for liver malignancy diagnosis using ultrasound images and video frames.

Recent developments of deep learning methods have demonstrated their feasibility in liver malignancy diagnosis using ultrasound (US) images. However, most of these methods require manual selection and annotation of US images by radiologists, which limit their practical application. On the other hand, US videos provide more comprehensive morphological information about liver masses and their relationships with surrounding structures than US images, potentially leading to a more accurate diagnosis. Here, we developed a fully automated artificial intelligence (AI) pipeline to imitate the workflow of radiologists for detecting liver masses and diagnosing liver malignancy. In this pipeline, we designed an automated mass-guided strategy that used segmentation information to direct diagnostic models to focus on liver masses, thus increasing diagnostic accuracy. The diagnostic models based on US videos utilized bi-directional convolutional long short-term memory modules with an attention-boosted module to learn and fuse spatiotemporal information from consecutive video frames. Using a large-scale dataset of 50 063 US images and video frames from 11 468 patients, we developed and tested the AI pipeline and investigated its applications. A dataset of annotated US images is available at https://doi.org/10.5281/zenodo.7272660.

Targeting KRAS in gynecological malignancies.

Cervical, endometrial, and ovarian cancers stand prominently as the leading gynecological malignancies of the female reproductive system. The conventional therapeutic modalities for gynecological malignancies have predominantly encompassed surgery, chemotherapy, and radiotherapy. However, efficacy of these approaches remains limited in cases of relapse or drug resistance. KRAS is one of the most frequently mutated oncogenes in human cancers. The KRAS gene encodes a small guanosine triphosphatase protein that acts as a molecular switch for crucial intracellular signaling pathways. KRAS mutations are deeply involved in the occurrence and development of gynecological malignancies. The present review aims to expound upon the role of oncogenic KRAS as a biomarker, elucidating various therapeutic approaches under investigation targeting the KRAS pathway in gynecological tumors.

Hypercalcemia and cancer: Differential diagnosis and treatment.

Incidentally detected hypercalcemia usually presents in an indolent manner and is most likely caused by primary hyperparathyroidism. In contrast, hypercalcemia in the patient with a history of cancer presents in a wide range of clinical settings and may be severe enough to warrant hospitalization. This form of hypercalcemia is usually secondary to hypercalcemia of malignancy and can be fatal. Hypercalcemia of malignancy is most commonly mediated by tumoral production of parathyroid hormone-related protein or by cytokines activating osteoclast degradation of bone. The initial workup, differential diagnoses, confirmatory laboratory testing, imaging, and medical and surgical management of hypercalcemia are described in the patient with cancer.

Circular RNAs in EMT-driven metastasis regulation: modulation of cancer cell plasticity, tumorigenesis and therapy resistance.

The non-coding RNAs comprise a large part of human genome lack of capacity in encoding functional proteins. Among various members of non-coding RNAs, the circular RNAs (circRNAs) have been of importance in the pathogenesis of human diseases, especially cancer. The circRNAs have a unique closed loop structure and due to their stability, they are potential diagnostic and prognostic factors in cancer. The increasing evidences have highlighted the role of circRNAs in the modulation of proliferation and metastasis of cancer cells. On the other hand, metastasis has been responsible for up to 90% of cancer-related deaths in patients, requiring more investigation regarding the underlying mechanisms modulating this mechanism. EMT enhances metastasis and invasion of tumor cells, and can trigger resistance to therapy. The cells demonstrate dynamic changes during EMT including transformation from epithelial phenotype into mesenchymal phenotype and increase in N-cadherin and vimentin levels. The process of EMT is reversible and its reprogramming can disrupt the progression of tumor cells. The aim of current review is to understanding the interaction of circRNAs and EMT in human cancers and such interaction is beyond the regulation of cancer metastasis and can affect the response of tumor cells to chemotherapy and radiotherapy. The onco-suppressor circRNAs inhibit EMT, while the tumor-promoting circRNAs mediate EMT for acceleration of carcinogenesis. Moreover, the EMT-inducing transcription factors can be controlled by circRNAs in different human tumors.

Tracing the cis-regulatory changes underlying the endometrial control of placental invasion.

Among eutherian (placental) mammals, placental embedding into the maternal endometrium exhibits great differences, from being deeply invasive (e.g., humans) to noninvasive (e.g., cattle). The degree of invasion of placental trophoblasts is positively correlated with the rate of cancer malignancy. Previously, we have shown that fibroblasts from different species offer different levels of resistance to the invading trophoblasts as well as to cancer cell invasion. Here we present a comparative genomic investigation revealing cis-regulatory elements underlying these interspecies differences in invasibility. We identify transcription factors that regulate proinvasibility and antiinvasibility genes in stromal cells. Using an in vitro invasibility assay combined with CRISPR-Cas9 gene knockout, we found that the transcription factors GATA2 and TFDP1 strongly influence the invasibility of endometrial and skin fibroblasts. This work identifies genomic mechanisms explaining species differences in stromal invasibility, paving the way to therapies targeting stromal characteristics to regulate placental invasion, wound healing, and cancer dissemination.

A mucus production programme promotes classical pancreatic ductal adenocarcinoma.

OBJECTIVE: The optimal therapeutic response in cancer patients is highly dependent upon the differentiation state of their tumours. Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer that harbours distinct phenotypic subtypes with preferential sensitivities to standard therapies. This study aimed to investigate intratumour heterogeneity and plasticity of cancer cell states in PDA in order to reveal cell state-specific regulators. DESIGN: We analysed single-cell expression profiling of mouse PDAs, revealing intratumour heterogeneity and cell plasticity and identified pathways activated in the different cell states. We performed comparative analysis of murine and human expression states and confirmed their phenotypic diversity in specimens by immunolabeling. We assessed the function of phenotypic regulators using mouse models of PDA, organoids, cell lines and orthotopically grafted tumour models. RESULTS: Our expression analysis and immunolabeling analysis show that a mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of PDA - the most common differentiation state. SPDEF maintains the classical differentiation and supports PDA transformation in vivo. The SPDEF tumour-promoting function is mediated by its target genes AGR2 and ERN2/IRE1ß that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation. CONCLUSIONS: Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants.

Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: Oncogenic 'hotspot' mutations of KRAS and GNAS are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific Kras G12D and Gnas R201C co-expression in p48Cre; KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-GnasR201C) mice ('Kras;Gnas' mice) caused development of cystic lesions recapitulating IPMNs. OBJECTIVE: We aim to unveil the consequences of mutant Gnas R201C expression on phenotype, transcriptomic profile and genomic dependencies. DESIGN: We performed multimodal transcriptional profiling (bulk RNA sequencing, single-cell RNA sequencing and spatial transcriptomics) in the 'Kras;Gnas' autochthonous model and tumour-derived cell lines (Kras;Gnas cells), where Gnas R201C expression is inducible. A genome-wide CRISPR/Cas9 screen was conducted to identify potential vulnerabilities in KrasG12D;GnasR201C co-expressing cells. RESULTS: Induction of Gnas R201C-and resulting G(s)alpha signalling-leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genes Gpi1 and Slc2a1 in Kras G12D;Gnas R201C co-expressing cells. Real-time metabolic analyses in Kras;Gnas cells and autochthonous Kras;Gnas model confirmed enhanced glycolysis on Gnas R201C induction. Induction of Gnas R201C made Kras G12D expressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis on Gnas R201C induction. CONCLUSION: Multiple orthogonal approaches demonstrate that Kras G12D and Gnas R201C co-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs.

Rheumatoid arthritis reduces the risk of colorectal cancer through immune inflammation mediation.

There is a close relationship between immune-mediated inflammation and cancer, and there is still controversy over whether rheumatoid arthritis (RA) increases the risk of malignancy. We first used Mendelian randomization (MR) analysis to explore the potential causal relationship between RA and pan-cancer. And verify the effect of immune-mediated inflammation on cancer through intermediate MR analysis. Then we extracted the standardized incidence rate of malignancy in RA patients relative to the general population through large-scale meta-analysis. Finally, we performed pan-cancer analysis on the RA related genes obtained from MR analysis. And perform immune related analysis on key genes to reveal the association between RA and malignancy. The MR analysis demonstrated a negative correlation between RA and pan-cancer (p = 0.008). Autoimmune traits were the main mediating variable for the causal relationship between RA and pan-cancer. Based on the results of the meta-analysis, we validated that RA reduces the risk of developing colorectal cancer (SIR = 0.69, 95% CI 0.53-0.85). Pan-cancer analysis also showed that high expression of RA related genes was negatively correlated with colon adenocarcinoma. IL6R was the gene with the highest correlation among them, and its correlation with immune cells was higher in colorectal cancer than in other malignancy. Our MR study provides evidence that RA was associated with reduced risk of colorectal cancer. This effect is caused by immune-mediated inflammation, with IL6R being a key regulatory gene.

False-Reactive Fourth-Generation Human Immunodeficiency Virus Testing in Cancer Patients.

BACKGROUND: The fourth-generation (4th-gen) human immunodeficiency virus (HIV)-1/2 antibody/antigen (Ab/Ag) combination immunoassay currently used for HIV screening offers greater sensitivity than previous assays, but false-reactive results occur in up to 20% of patients. Large-scale observations in cancer patients are lacking. METHODS: We conducted a retrospective study of cancer patients seen at the University of Texas MD Anderson Cancer Center (March 2016-January 2023) who had reactive 4th-gen ARCHITECT HIV-1/2 Ab/Ag combination immunoassay results. We analyzed characteristics of patients with true-reactive and false-reactive results, defined based on Centers for Disease Control and Prevention criteria. RESULTS: A total of 43 637 patients underwent 4th-gen HIV screening, and 293 had reactive 4th-gen HIV test results. Twenty-one patients were excluded because they did not have cancer. Among the remaining 272 patients, 78 (29%) had false-reactive results. None of these patients experienced delays in their cancer treatment, but 26% experienced mental distress. Multivariate logistic regression analysis identified 5 predictors of having false-reactive results: age >60 years (adjusted odds ratio [aOR], 6.983; P < .0001), female sex (aOR, 6.060; P < .0001), race/ethnicity (Black: aOR, 0.274; Hispanic: aOR, 0.236; P = .002), syphilis coinfection (aOR, 0.046; P = .038), and plant alkaloids therapy (aOR, 2.870; P = .013). CONCLUSIONS: False-reactive 4th-gen HIV test results occur in almost one-third of cancer patients. Physicians should be aware of the high rates of false-reactive HIV screening results in this patient population. These findings may have implications for counseling regarding testing, especially among those at low risk for HIV infection.

Plasma Microbial Cell-Free DNA Sequencing in Immunocompromised Patients With Pneumonia: A Prospective Observational Study.

BACKGROUND: Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia. METHODS: In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing. Pneumonia etiology was adjudicated by a blinded independent committee. The primary outcome, additive diagnostic value, was assessed in the Per Protocol population (patients with complete testing results and no major protocol deviations) and defined as the percent of patients with an etiology of pneumonia exclusively identified by plasma microbial cell-free DNA sequencing. Clinical additive diagnostic value was assessed in the Per Protocol subgroup with negative usual care testing. RESULTS: Of 257 patients, 173 met Per Protocol criteria. A pneumonia etiology was identified by usual care in 52/173 (30.1%), plasma microbial cell-free DNA sequencing in 49/173 (28.3%) and the combination of both in 73/173 (42.2%) patients. Plasma microbial cell-free DNA sequencing exclusively identified an etiology of pneumonia in 21/173 patients (additive diagnostic value 12.1%, 95% confidence interval [CI], 7.7% to 18.0%, P < .001). In the Per Protocol subgroup with negative usual care testing, plasma microbial cell-free DNA sequencing identified a pneumonia etiology in 21/121 patients (clinical additive diagnostic value 17.4%, 95% CI, 11.1% to 25.3%). CONCLUSIONS: Non-invasive plasma microbial cell-free DNA sequencing significantly increased diagnostic yield in immunocompromised patients with pneumonia undergoing bronchoscopy and extensive microbiologic and molecular testing. CLINICAL TRIALS REGISTRATION: NCT04047719.

Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral-Treated People With Human Immunodeficiency Virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear. METHODS: We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality. RESULTS: CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/µL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies. CONCLUSIONS: In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.

Multicenter Retrospective Study of Invasive Fusariosis in Intensive Care Units, France.

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002----2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

High malignancy rate in IgE-deficient children.

Recent epidemiological studies have increasingly highlighted the antitumor efficacy of IgE owing to the increased malignancy rate in IgE-deficient patients. The purpose of this study, the largest for children, was to determine whether malignant diagnoses in children are associated with IgE deficiency (IgE <2.5 kIU/L). A total of 6821 pediatric patients were reviewed, focusing on patients with IgE below 2.5 kIU/L (n = 599). The causes of IgE testing were evaluated by categorizing them as having cancer, allergies, suspected or diagnosed immunodeficiency, and other conditions. In all but one patient with malignancy, IgE levels were measured after the diagnosis of the disease. Malignancies were observed much more frequently in the low IgE group than in the normal group (10/599, 1.7% and 7/6222, 0.11%; OR = 15.07; 95% CI: 5.72-39.75; p <.0001). According to our analysis, 70% of the patients had leukemia/lymphoma, which is consistent with studies showing that hematologic malignancies are the most frequent cancers linked to IgE deficiency. No increase in the prevalence of cancer was observed in IgE-deficient patients with suspected or diagnosed immunodeficiency. In conclusion, we observed a higher rate of previous malignancy (particularly hematologic cancer) in children with low serum IgE levels. Larger investigations would offer insightful information about the function of low IgE levels in predicting malignancy risk and improving the present diagnostic procedures.

Natural resistance to cancer: A window of hope.

As healthcare systems are improving and thereby the life expectancy of human populations is increasing, cancer is representing itself as the second leading cause of death. Although cancer biologists have put enormous effort on cancer research so far, we still have a long way to go before being able to treat cancers efficiently. One interesting approach in cancer biology is to learn from natural resistance and/or predisposition to cancer. Cancer-resistant species and tissues are thought-provoking models whose study shed light on the inherent cancer resistance mechanisms that arose during the course of evolution. On the other hand, there are some syndromes and factors that increase the risk of cancer development, and revealing their underlying mechanisms will increase our knowledge about the process of cancer formation. Here, we review natural resistance and predisposition to cancer and the known mechanisms at play. Further insights from these natural phenomena will help design future cancer research and could ultimately lead to the development of novel cancer therapeutic strategies.