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Background: Despite limited scientific evidence, public perceptions of cannabis as health enhancing are significant. As food products, cannabis edibles (edibles), may also leverage food-related associations that convey health. Social media is a prominent and influential source of largely unregulated cannabis information and a potential place to correct misinformation. Given its potential to shape product appeal and perceptions of health benefits and risks, understanding the social media landscape around edibles and health is a priority., Methods: We conducted a quantitative content analysis of a random sample of #edibles Instagram posts (N = 702) published in January 2020. A structured coding instrument analyzed posts for: (1) non-food related health, medicine, and wellness content (2) food-related characteristics/associations suggesting edibles are healthy foods or appropriate for particular diets., Results: The majority of posts (61%) featured non-food related health, medicine, or wellness content. 35% of posts noted a general health or wellness issue or benefit, while 9% highlighted a medical condition, clinical diagnosis or attendant benefit; a wide range of wellness, health, and clinical issues were cited. Nearly half of all posts (45%) alluded to medicine or being medicated, while 22% referenced medical marijuana specifically. Connections to health were also made through food-related associations, with 13% of posts citing a dietary need or nutrient claim and 10% highlighting food-related characteristics that imply product healthfulness., Conclusions: Health-related content is widespread among #edibles Instagram posts. Communication approaches to counter unsubstantiated health claims and regulatory strategies limiting commercial promotion should be considered. Explicit connections between edibles and health and more implicit associations via hashtags and images warrant particular attention.

Background: Black patients were severely under-represented in the clinical trials that led to the approval of immune checkpoint inhibitors (ICIs) for all cancers. The aim of this study was to characterise the effectiveness and safety of ICIs in Black patients., Methods: We did a retrospective cohort study of patients in the US Veterans Health Administration (VHA) system's Corporate Data Warehouse containing electronic medical records for all patients who self-identified as non-Hispanic Black or African American (referred to as Black) or non-Hispanic White (referred to as White) and received PD-1, PD-L1, CTLA-4, or LAG-3 inhibitors between Jan 1, 2010, and Dec 31, 2023. Effectiveness outcomes were overall survival, time to treatment discontinuation, and time to next treatment. The safety outcome was the frequency of immune-related adverse events; assessed among a random sample of 1000 Black patients and 1000 White patients, 892 pairs were matched on the basis of baseline characteristics using 1:1 exact matching without replacement. After manual chart review, patients who did not receive ICI therapy or who had inadequate follow-up were excluded. The adjusted effect of race on each effectiveness outcome was assessed in the whole ICI-treated cohort with propensity-weighted Cox regression with robust standard errors. Immune-related adverse events outcomes were analysed in the random matched sample with multivariable Cox regression, adjusting for baseline characteristics., Findings: We identified 26 398 patients, of whom 4943 (18·7%) patients were Black, 21 455 (81·3%) were White, 895 (3·4%) were female, 25 503 (96·6%) were male, 11 859 (45%) had non-small-cell lung cancer, and 26 045 (98·7%) received PD-1 or PD-L1 inhibitors. As of data cutoff (Aug 28, 2024), median follow-up was 40·3 months (95% CI 38·3-42·3) for Black patients and 43·9 months (43·0-45·1) for White patients. Compared with White patients, Black patients had longer time to treatment discontinuation (2-year unadjusted rates 10·7% [95% CI 9·8-11·7] for Black patients vs 8·6% [8·2-9·0] for White patients; adjusted hazard ratio [HR] 0·91, 95% CI 0·87-0·95, p<0·0001), similar time to next treatment (23·5% [22·3-24·8] for Black patients vs 25·6% [25·0-26·2] for White patients; 1·00, 0·95-1·05, p=0·96), and slightly improved overall survival (36·5% [35·2-38·1] for Black patients vs 36·5% [35·8-37·1]; 0·95, 0·90-0·99, p=0·036). 1710 patients (n=862 Black and n=848 White) were analysed for safety outcomes. Compared with White patients, Black patients had a reduced risk of all-grade immune-related adverse events (unadjusted 2-year rate 33·1% [95% CI 28·9-37·1] vs 44·1% [95% CI 39·1-48·7]; adjusted HR 0·75, 95% CI 0·62-0·90, p=0·0026), immune-related adverse events requiring treatment with systemic steroids (0·61, 0·46-0·81, p=0·00051), and immune-related adverse events resulting in permanent ICI discontinuation (0·58, 0·44-0·78, p=0·00024). In exploratory analyses of irAE subtypes, a significant risk reduction in Black patients was found for colitis (0·46, 0·27-0·76, p=0·0026) and hyperthyroidism or hypothyroidism (0·63, 0·44-0·90, p=0·011), and no significant differences were found for any other immune-related adverse event subtypes analysed. Similar results were found in analyses using a steroid-based definition of immune-related adverse events among the entire ICI-treated cohort., Interpretation: Compared with White patients, Black patients had similar ICI effectiveness and lower toxicities among those treated in the national VHA system, potentially reflecting an important difference in the therapeutic ratio (ratio of benefit to harm) of ICIs. Our findings of decreased toxicity among Black patients require further investigation to assess their generalisability., Funding: Million Veteran Program, Office of Research and Development, Veterans Health Administration and the LUNGevity foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright Published by Elsevier Ltd.)

Purpose: Local failure rates after treatment for locally advanced non-small cell lung cancer (NSCLC) remain high. Efforts to improve local control with a uniform dose escalation or dose escalation to midtreatment positron emission tomography (PET)-avid residual disease have been limited by heightened toxicity. This trial aimed to refine response-based adaptive radiation therapy (RT) and minimize toxicity by incorporating fluorodeoxyglucose-PET (FDG-PET) and ventilation-perfusion single-photon emission computed tomography (SPECT) imaging midtreatment., Methods and Materials: A total of 47 patients with stage IIA to III unresectable NSCLC were prospectively enrolled in this single-institution trial (NCT02492867). Patients received concurrent chemoradiation therapy with personalized response-based adaptive RT over 30 fractions incorporating ventilation-perfusion single-photon emission computed tomography and FDG-PET. The first 21 fractions (46.2 Gy at 2.2 Gy/fraction) were delivered to the tumor while minimizing the dose to the SPECT-defined functional lung. The plan was then adapted for the final 9 fractions (2.2-3.8 Gy/fraction) up to a total of 80.4 Gy, based on the midtreatment FDG-PET tumor response to escalate the dose to the residual tumor while minimizing the dose to the SPECT-defined functional lung. Nonprogressing patients received consolidative carboplatin, paclitaxel, or durvalumab. The primary endpoint of the study was ≥ grade 2 lung and esophageal toxicities. Secondary endpoints included time to local progression, tumor response, and overall survival., Results: At 1 year posttreatment, the rates of grade 2 and grade 3 pneumonitis were 21.3% and 2.1%, respectively, with no difference in pneumonitis rates among patients who received and did not receive adjuvant durvalumab (P = .74). Although there were no grade 3 esophageal-related toxicities, 66.0% of patients experienced grade 2 esophagitis. The 1- and 2-year local control rates were 94.5% (95% CI, 87.4%-100%) and 87.5% (95% CI, 76.7%-100%), respectively. Overall survival was 82.8% (95% CI, 72.6%-94.4%) at 1 year and 62.3% (95% CI, 49.6%-78.3%) at 2 years., Conclusions: Response-based adaptive dose-escalation accounting for tumor change and normal tissue function during treatment provided excellent local control, comparable toxicity to standard chemoradiation therapy, and did not increase toxicity with adjuvant immunotherapy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Barth syndrome (BTHS) is a rare, infantile-onset, X-linked mitochondriopathy exhibiting a variable presentation of failure to thrive, growth insufficiency, skeletal myopathy, neutropenia, and heart anomalies due to mitochondrial dysfunction secondary to inherited TAFAZZIN transacetylase mutations. Although not reported in BTHS patients, male infertility is observed in several Tafazzin ( Taz ) mouse alleles and in a Drosophila mutant. Herein, we examined the male infertility phenotype in a BTHS-patient-derived D75H point-mutant knockin mouse ( Taz PM ) allele that expresses a mutant protein lacking transacetylase activity. Neonatal and adult Taz PM testes were hypoplastic, and their epididymis lacked sperm. Histology and biomarker analysis revealed Taz PM spermatogenesis is arrested prior to sexual maturation due to an inability to undergo meiosis and the generation of haploid spermatids. Moreover, Taz PM testicular mitochondria were found to be structurally abnormal, and there was an elevation of p53-dependent apoptosis within Taz PM seminiferous tubules. Immunoblot analysis revealed that Taz PM gamete genome integrity was compromised, and both histone γ-H2Ax and Nucleoside diphosphate kinase-5 protein expression were absent in juvenile Taz PM testes when compared to controls. We demonstrate that Taz-mediated transacetylase activity is required within mitochondria for normal spermatogenesis, and its absence results in meiotic arrest. We hypothesize that elevated Taz PM spermatogonial apoptosis causes azoospermia and complete infertility.

Background: The cumulative, health system-wide survival benefit of immune checkpoint inhibitors (ICIs) is unclear, particularly among real-world patients with limited life expectancies and among subgroups poorly represented on clinical trials. We sought to determine the health system-wide survival impact of ICIs., Methods: We identified all patients receiving PD-1/PD-L1 or CTLA-4 inhibitors from 2010 to 2023 in the national Veterans Health Administration (VHA) system (ICI cohort) and all patients who received non-ICI systemic therapy in the years before ICI approval (historical control). ICI and historical control cohorts were matched on multiple cancer-related prognostic factors, comorbidities, and demographics. The effect of ICI on overall survival was quantified with Cox regression incorporating matching weights. Cumulative life-years gained system-wide were calculated from the difference in adjusted 5-year restricted mean survival times., Results: There were 27,322 patients in the ICI cohort and 69,801 patients in the historical control cohort. Among ICI patients, the most common cancer types were NSCLC (46%) and melanoma (10%). ICI demonstrated a large OS benefit in most cancer types with heterogeneity across cancer types (NSCLC: adjusted HR [aHR] 0.56, 95% confidence interval [CI] 0.54-0.58, p < 0.001; urothelial: aHR 0.91, 95% CI 0.83-1.01, p = 0.066). The relative benefit of ICI was stable across patient age, comorbidity, and self-reported race subgroups. Across VHA, 15,859 life-years gained were attributable to ICI within 5-years of treatment, with NSCLC contributing the most life-years gained., Conclusion: We demonstrated substantial increase in survival due to ICIs across a national health system, including in patient subgroups poorly represented on clinical trials., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Abstract: As survival rates improve for patients with metastatic disease, more patients are requiring complex treatment for brain metastases. Stereotactic radiosurgery (SRS) is a conformal radiotherapy technique that allows high ablative dose to be delivered to a specific target and is a standard effective local therapy for the treatment of patients with limited brain metastases. This review highlights the current landscape of SRS treatment in the context of modern therapeutic advances and identifies new research frontiers to personalize SRS and maximize the therapeutic ratio., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Post-treatment surveillance recommendations for oropharyngeal cancer do not vary with p16 status despite the differences in outcomes. The optimal algorithm personalizing follow-up for these patients remains undefined. Here, we evaluate the feasibility and utility of incorporating electronic patient-reported outcomes (ePROs) and circulating tumor DNA (ctDNA) into routine surveillance for patients treated for p16+ oropharynx cancer., Methods: A prospective registry was developed in which ePROs and ctDNA were incorporated into routine surveillance among patients with oropharynx cancer. ePROs were emailed monthly for 1 year and blood HPV ctDNA testing was performed every 3-6 months. The primary objective was to assess patient compliance with ePRO-based surveillance with adequate compliance defined as ≥85% of patients completing monthly ePROs. Sensitivity, specificity, and positive/negative predictive values to detect recurrence were calculated for ePROs, HPV ctDNA, or the combination., Results: Of 122 patients who initially expressed interest, 76 completed the electronic consent process and 44/76 (58%) were compliant with monthly surveys over 1 year; thus adequate compliance was not achieved. Technical difficulties associated with ePRO receipt through email largely limited participation. Provider feedback was significantly associated with heightened ePRO compliance. One hundred and six patients had ctDNA testing with a mean number of three tests per patient. Sensitivity to detect recurrence was 75% for the combination of ePROs and ctDNA., Conclusion: Despite lower than anticipated compliance with ePROs, our findings show promise for incorporation of HPV ctDNA into surveillance paradigms for HPV-related oropharynx cancer with suggestions of methods to optimize ePRO formats for personalized surveillance., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: Despite randomized trials demonstrating a mortality benefit to low-dose computed tomography screening to detect lung cancer, uptake of lung cancer screening (LCS) has been slow, and the benefits of screening remain unclear in clinical practice., Methods: This study aimed to assess the impact of screening among patients in the Veterans Health Administration (VA) health care system diagnosed with lung cancer between 2011 and 2018. Lung cancer stage at diagnosis, lung cancer-specific survival, and overall survival between patients with cancer who did and did not receive screening before diagnosis were evaluated. We used Cox regression modeling and inverse propensity weighting analyses with lead time bias adjustment to correlate LCS exposure with patient outcomes., Results: Of 57,919 individuals diagnosed with lung cancer in the VA system between 2011 and 2018, 2167 (3.9%) underwent screening before diagnosis. Patients with screening had higher rates of stage I diagnoses (52% vs. 27%; p ≤ .0001) compared to those who had no screening. Screened patients had improved 5-year overall survival rates (50.2% vs. 27.9%) and 5-year lung cancer-specific survival (59.0% vs. 29.7%) compared to unscreened patients. Among screening-eligible patients who underwent National Comprehensive Cancer Network guideline-concordant treatment, screening resulted in substantial reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79; 95% confidence interval [CI], 0.67-0.92; p = .003) and lung-specific mortality (aHR, 0.61; 95% CI, 0.50-0.74; p < .001)., Conclusions: While LCS uptake remains limited, screening was associated with earlier stage diagnoses and improved survival. This large national study corroborates the value of LCS in clinical practice; efforts to widely adopt this vital intervention are needed., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked Tafazzin (TAZ) gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific TAZ mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored CRISPR/Cas9 knock-in mouse allele ( Taz PM ) that phenocopies BTHS clinical traits. As Taz PM males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile Taz PM males exhibit mild left ventricular dilation in systole but have unaltered fatty acid/amino acid metabolism and normal adenosine triphosphate (ATP). This occurs in concert with a hyperactive p53 pathway, elevation of cardioprotective antioxidant pathways, and induced autophagy-mediated early senescence in juvenile Taz PM hearts. However, adult Taz PM males exhibit chronic heart failure with reduced growth and ejection fraction, cardiac fibrosis, reduced ATP, and suppressed fatty acid/amino acid metabolism. This biphasic changeover from a mild-to-severe heart phenotype coincides with p53 suppression, downregulation of cardioprotective antioxidant pathways, and the onset of terminal senescence in adult Taz PM hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.

Purpose: Adjuvant durvalumab after definitive chemoradiotherapy (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) is well-tolerated in clinical trials. However, pneumonitis rates outside of clinical trials remain poorly defined with CRT followed by durvalumab. We aimed to describe the influence of durvalumab on pneumonitis rates among a large cohort of patients with stage III NSCLC., Methods and Materials: We studied patients with stage III NSCLC in the national Veterans Health Administration from 2015 to 2021 who received concurrent CRT alone or with adjuvant durvalumab. We defined pneumonitis as worsening respiratory symptoms with radiographic changes within 2 years of CRT and graded events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. We used Cox regression to analyze risk factors for pneumonitis and the effect of postbaseline pneumonitis on overall survival., Results: Among 1994 patients (989 CRT alone, 1005 CRT followed by adjuvant durvalumab), the 2-year incidence of grade 2 or higher pneumonitis was 13.9% for CRT alone versus 22.1% for CRT plus durvalumab (unadjusted P < .001). On multivariable analysis, durvalumab was associated with higher risk of grade 2 pneumonitis (hazard ratio, 1.45; 95% CI, 1.09-1.93; P = .012) but not grade 3 to 5 pneumonitis (P = .2). Grade 3 pneumonitis conferred worse overall survival (hazard ratio, 2.51; 95% CI, 2.06-3.05; P < .001) but grade 2 pneumonitis did not (P = .4)., Conclusions: Adjuvant durvalumab use was associated with increased risk of low-grade but not higher-grade pneumonitis. Reassuringly, low-grade pneumonitis did not increase mortality risk. We observed increased rates of high-grade pneumonitis relative to clinical trials; the reasons for this require further study., (Published by Elsevier Inc.)

Aims: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. Results: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Innovation: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Conclusions: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. Antioxid. Redox Signal . 39, 942-956.

The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13 C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth., Significance: This study is the first to directly measure biosynthetic flux in both glioma and cortical tissue in human brain cancer patients. Brain tumors rewire glucose carbon utilization away from oxidation and neurotransmitter production towards biosynthesis to fuel growth. Blocking these metabolic adaptations with dietary interventions slows brain cancer growth with minimal effects on cortical metabolism.

Immune checkpoint inhibitors, a class of drugs used in approximately forty unique cancer indications, are a sizable component of the economic burden of cancer care in the US. Instead of personalized weight-based dosing, immune checkpoint inhibitors are most commonly administered at "one-size-fits-all" flat doses that are higher than necessary for the vast majority of patients. We hypothesized that personalized weight-based dosing along with common stewardship efforts at the pharmacy level, such as dose rounding and vial sharing, would lead to reductions in immune checkpoint inhibitor use and lower spending. Using data from the Veterans Health Administration (VHA) and Medicare drug prices, we estimated reductions in immune checkpoint inhibitor use and spending that would be associated with pharmacy-level stewardship strategies, in a case-control simulation study of individual patient-level immune checkpoint inhibitor administration events. We identified baseline annual VHA spending for these drugs of approximately $537 million. Combining weight-based dosing, dose rounding, and pharmacy-level vial sharing would generate expected annual VHA health system savings of $74 million (13.7 percent). We conclude that adoption of pharmacologically justified immune checkpoint inhibitor stewardship measures would generate sizable reductions in spending for these drugs. Combining these operational innovations with value-based drug price negotiation enabled by recent policy changes may improve the long-term financial viability of cancer care in the US.

Despite the recent rise of RNA-seq datasets combining single-cell (sc) resolution with 4-thiouridine (4sU) labelling, analytical methods exploiting their power to dissect transcriptional bursting are lacking. Here, we present a mathematical model and Bayesian inference implementation to facilitate genome-wide joint parameter estimation and confidence quantification (R package: burstMCMC). We demonstrate that, unlike conventional scRNA-seq, 4sU scRNA-seq resolves temporal parameters and furthermore boosts inference of dimensionless parameters via a synergy between single-cell resolution and 4sU labelling. We apply our method to published 4sU scRNA-seq data and linked with ChIP-seq data, we uncover previously obscured associations between different parameters and histone modifications., (© 2023. The Author(s).)

Purpose: Cannabis use rates are increasing in the United States. Patients with cancer use cannabis for many reasons, even without high-quality supporting data. This study sought to characterize cannabis use among patients seen in radiation oncology in a state that has legalized adult nonmedical use cannabis and to identify key cannabis-related educational topics., Methods and Materials: Cannabis history was documented by providers using a structured template at patient visits in an academic radiation oncology practice October 2020 to November 2021. Cannabis use data, including recency/frequency of use, reason, and mode of administration, were summarized, and logistic regression was used to explore associations between patient and disease characteristics and recent cannabis use. A multivariable model employed stepwise variable selection using the Akaike Information Criterion., Results: Of 3143 patients total, 91 (2.9%) declined to answer cannabis use questions, and 343 (10.9%) endorsed recent use (≤1 month ago), 235 (7.5%) noted nonrecent use (>1 month ago), and 2474 (78.7%) denied history of cannabis use. In multivariable analyses, those ≥50 years old (odds ratio [OR], 0.409; 95% confidence interval [CI], 0.294-0.568; P < .001) or with history of prior courses of radiation (OR, 0.748; 95% CI, 0.572-0.979; P = .034) were less likely, and those with a mental health diagnosis not related to substance use (OR, 1.533; 95% CI, 1.171-2.005; P = .002) or who smoked tobacco (OR, 3.003; 95% CI, 2.098-4.299; P < .001) were more likely to endorse recent cannabis use. Patients reported pain, insomnia, and anxiety as the most common reasons for use. Smoking was the most common mode of administration., Conclusions: Patients are willing to discuss cannabis use with providers and reported recent cannabis use for a variety of reasons. Younger patients new to oncologic care and those with a history of mental illness or tobacco smoking may benefit most from discussions about cannabis given higher rates of cannabis use in these groups., (Copyright © 2022 American Society for Radiation Oncology. All rights reserved.)

The genome of cowpoxvirus (CPXV) could be considered prototypical for orthopoxviridae (OXPV) since it contains many open reading frames (ORFs) absent or lost in other OPXV, including vaccinia virus (VACV). These additional ORFs are non-essential for growth in vitro but are expected to contribute to the broad host range, virulence and immune evasion characteristics of CPXV. For instance, unlike VACV, CPXV encodes proteins that interfere with T cell stimulation, either directly or by preventing antigen presentation or co-stimulation. When studying the priming of naïve T cells, we discovered that CPXV, but not VACV, encodes a secreted factor that interferes with activation and proliferation of naïve CD8+ and CD4+ T cells, respectively, in response to anti-CD3 antibodies, but not to other stimuli. Deletion mapping revealed that the inhibitory protein is encoded by CPXV14, a small secreted glycoprotein belonging to the poxvirus immune evasion (PIE) family and containing a smallpoxvirus encoded chemokine receptor (SECRET) domain that mediates binding to chemokines. We demonstrate that CPXV14 inhibition of antibody-mediated T cell activation depends on the presence of Fc-gamma receptors (FcγRs) on bystander cells. In vitro, CPXV14 inhibits FcγR-activation by antigen/antibody complexes by binding to FcγRs with high affinity and immobilized CPXV14 can trigger signaling through FcγRs, particularly the inhibitory FcγRIIB. In vivo, CPXV14-deleted virus showed reduced viremia and virulence resulting in reduced weight loss and death compared to wildtype virus whereas both antibody and CD8+ T cell responses were increased in the absence of CPXV14. Furthermore, no impact of CPXV14-deletion on virulence was observed in mice lacking the inhibitory FcγRIIB. Taken together our results suggest that CPXV14 contributes to virulence and immune evasion by binding to host FcγRs., Competing Interests: The authors have declared that no competing interests exist.

This review article highlights the treatment paradigms for early-stage endometrial cancer with a focus on the role of external beam radiation therapy. We aim for this review to serve as an introductory resource for gynecological oncologists, radiation oncologists, medical oncologists, and other practitioners to understand the treatments for this disease. The main treatment of endometrial cancer is surgical resection with total hysterectomy and bilateral salpingo-oophorectomy. The benefit of adjuvant radiation after surgery is primarily to prevent local recurrence. Patients with low risk of recurrence can be observed post-operatively. Vaginal cuff brachytherapy, which has been shown to be equally effective as pelvic radiation with fewer side effects, is typically recommended for high-intermediate risk patients (with characteristics such as lymphovascular space invasion, high grade, or significant myometrial invasion). In the adjuvant setting, pelvic radiation therapy is reserved for patients who have deeply invasive stage I grade 2 or 3 disease, stage II disease, and non-endometrioid histologies. In patients who are not medically operable, definitive treatment consists of brachytherapy±pelvic external beam radiation therapy. We have highlighted the main acute and long-term side effects of pelvic radiation as well as recommendations for symptom management and summarized promising evidence showing improved rates of toxicities with more conformal radiation techniques., Competing Interests: Competing interests: SJ: consultant/advisory board for Varian and AstraZeneca., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The Fanconi anemia (FA) pathway safeguards genomic stability through cell cycle regulation and DNA damage repair. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established, but their function in mitosis is incompletely understood. Here, we performed a kinome-wide synthetic lethality screen in FANCA -/- fibroblasts, which revealed multiple mitotic kinases as necessary for survival of FANCA-deficient cells. Among these kinases, we identified the depletion of the centrosome kinase SIK2 as synthetic lethal upon loss of FANCA. We found that FANCA colocalizes with SIK2 at multiple mitotic structures and regulates the activity of SIK2 at centrosomes. Furthermore, we found that loss of FANCA exacerbates cell cycle defects induced by pharmacological inhibition of SIK2, including impaired G2-M transition, delayed mitotic progression, and cytokinesis failure. In addition, we showed that inhibition of SIK2 abrogates nocodazole-induced prometaphase arrest, suggesting a novel role for SIK2 in the spindle assembly checkpoint. Together, these findings demonstrate that FANCA-deficient cells are dependent upon SIK2 for survival, supporting a preclinical rationale for targeting of SIK2 in FA-disrupted cancers., (© 2021 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Although the RNA helicase Upf1 has hitherto been examined mostly in relation to its cytoplasmic role in nonsense mediated mRNA decay (NMD), here we report high-throughput ChIP data indicating genome-wide association of Upf1 with active genes in Schizosaccharomyces pombe. This association is RNase sensitive, correlates with Pol II transcription and mRNA expression levels. Changes in Pol II occupancy were detected in a Upf1 deficient (upf1Δ) strain, prevalently at genes showing a high Upf1 relative to Pol II association in wild-type. Additionally, an increased Ser2 Pol II signal was detected at all highly transcribed genes examined by ChIP-qPCR. Furthermore, upf1Δ cells are hypersensitive to the transcription elongation inhibitor 6-azauracil. A significant proportion of the genes associated with Upf1 in wild-type conditions are also mis-regulated in upf1Δ. These data envisage that by operating on the nascent transcript, Upf1 might influence Pol II phosphorylation and transcription., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo , the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2 . Fancc-/-;Mad2+/- mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than Fancc-/- mice. We utilized hematopoietic stem cell transplantation to propagate Fancc-/-; Mad2+/- AML in irradiated healthy mice to model FANCC -deficient AMLs arising in the non-FA population. Compared to cells from Fancc-/- mice, those from Fancc-/-;Mad2+/- mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of Fancc-/-;Mad2+/- mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in Fancc-/-; Mad2+/- mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies in vivo , show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Edwards, Mitchell, Abdul-Sater, Chan, Sun, Sheth, He, Jiang, Yuan, Sharma, Czader, Chin, Liu, de Cárcer, Nalepa, Broxmeyer, Clapp and Sierra Potchanant.)

Mitochondrial DNA (mtDNA) and plastid DNA (ptDNA) encode vital bioenergetic apparatus, and mutations in these organelle DNA (oDNA) molecules can be devastating. In the germline of several animals, a genetic "bottleneck" increases cell-to-cell variance in mtDNA heteroplasmy, allowing purifying selection to act to maintain low proportions of mutant mtDNA. However, most eukaryotes do not sequester a germline early in development, and even the animal bottleneck remains poorly understood. How then do eukaryotic organelles avoid Muller's ratchet-the gradual buildup of deleterious oDNA mutations? Here, we construct a comprehensive and predictive genetic model, quantitatively describing how different mechanisms segregate and decrease oDNA damage across eukaryotes. We apply this comprehensive theory to characterise the animal bottleneck with recent single-cell observations in diverse mouse models. Further, we show that gene conversion is a particularly powerful mechanism to increase beneficial cell-to-cell variance without depleting oDNA copy number, explaining the benefit of observed oDNA recombination in diverse organisms which do not sequester animal-like germlines (for example, sponges, corals, fungi, and plants). Genomic, transcriptomic, and structural datasets across eukaryotes support this mechanism for generating beneficial variance without a germline bottleneck. This framework explains puzzling oDNA differences across taxa, suggesting how Muller's ratchet is avoided in different eukaryotes., Competing Interests: The authors have declared that no competing interests exist.

Objective: To examine levels of parenting stress in mothers of preterm and term infants when the children were 2 years old; to determine the trajectory of stress over three time periods and to examine the association of maternal and neonatal factors and developmental outcomes with parenting stress., Design: It is a prospective longitudinal study to determine parenting stress in mothers of preterm and term infants with outcomes having been previously obtained at 4 and 12 months. At 2 years, 79 preterm mothers (96 babies) and 64 term mothers (77 babies) participated. The mothers completed the Parenting Stress Index-Short Form (PSI-SF), the Depression, Anxiety, Stress Scale (DASS) and the Child Behaviour Checklist (CBCL). The infants had a neurological examination and the Bayley-III scales were administered., Results: The mean total PSI-SF at 2 years was significantly higher for the preterm group compared with the term group of mothers (p=0.007). There was a significant increase in the mean total PSI over time for the preterm mothers (p<0.001). For mothers at 2 years, there was an association with high levels of parenting stress and abnormal scores on the DASS (p<0.001) and high total T-scores on the CBCL (internalising p<0.001; externalising p=0.006). There was no association between parenting stress and maternal demographics, neonatal factors or Bayley-III results., Conclusions: Parenting stress in mothers of preterm infants continues to be high at 2 years having increased over time. Maternal mental health problems and infant behavioural issues contribute to the stress., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Damping of magnetization dynamics in a ferromagnetic metal, arising from spin-orbit coupling, is usually characterised by the Gilbert parameter α. Recent calculations of this quantity, using a formula due to Kambersky, find that it is infinite for a perfect crystal owing to an intraband scattering term which is of third order in the spin-orbit parameter ξ. This surprising result conflicts with recent work by Costa and Muniz who study damping numerically by direct calculation of the dynamical transverse susceptibility in the presence of spin-orbit coupling. We resolve this inconsistency by following the approach of Costa and Muniz for a slightly simplified model where it is possible to calculate α analytically. We show that to second order in ξ one retrieves the Kambersky result for α, but to higher order one does not obtain any divergent intraband terms. The present work goes beyond that of Costa and Muniz by pointing out the necessity of including the effect of long-range Coulomb interaction in calculating damping for large ξ. A direct derivation of the Kambersky formula is given which shows clearly the restriction of its validity to second order in ξ so that no intraband scattering terms appear. This restriction has an important effect on the damping over a substantial range of impurity content and temperature. The experimental situation is discussed.

Unlabelled: There is a paucity of information on couple relationship quality in mothers of preterm infants during the first year of life., Aim: To determine couple relationship quality in mothers of very preterm infants in comparison to mothers of term infants and to examine maternal and infant factors associated with impaired couple relationship for the preterm mothers., Methods: At 4 and 12 months (corrected for prematurity for the preterm cohort), the mothers completed the Dyadic Adjustment Scale, the Edinburgh Postnatal Depression Scale, the Parenting Stress Index and the Short Temperament Scale. At 12 months, the infants had a neurodevelopmental assessment., Results: 86 mothers of preterm infants and 97 term mothers participated at 4 months, with 101 mothers of the preterm infants and 98 term mothers participating at 12 months. Comparisons of the two groups revealed no differences in Dyadic Adjustment or for any of the subscales. For the preterm mothers at 4 months, the independent variables associated with poor dyadic adjustment were ethnicity and higher levels of parenting stress. At 12 months, parenting stress was also an independent variable associated with impaired couple relationship., Conclusions: No differences in the incidence of poor quality couple relationship was found between mothers of very preterm and term infants. For preterm mothers, impaired couple relationship was associated with parenting stress., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aim: The aim of the study was to screen very preterm infants for autism spectrum disorder (ASD) with comparisons to a group of term controls. The study also aimed to identify maternal and neonatal risk factors, development and behaviour associated with a positive screen in the preterm group., Method: Preterm infants born ≤ 30 weeks gestation and term infants were recruited at two years of age. The mothers were posted the questionnaires and completed the Modified Checklist for Autism in Toddlers (M-CHAT), the Child Behaviour Checklist (CBCL) and the Depression, Anxiety and Stress Scales (DASS). Previously collected data from the mothers at 12 months--the Edinburgh Postnatal Depression Scales (EPDS) were analysed. The children had neurodevelopmental assessment including the Bayley-III. Infants positive on M-CHAT screen had an M-CHAT follow-up interview by phone and then were assessed by a developmental paediatrician as indicated with a diagnosis of autism being made on clinical judgement., Results: 13 (13.4%) of the 97 preterm infants screened positive on the M-CHAT compared to three (3.9%) of the 77 term infants (p = 0.036). On follow-up interview, three of the preterm infants remained positive (one was diagnosed with autism) compared to none of the term infants. The preterm infants who screened positive were born to younger, non-Caucasian mothers and were of lower birth weight and had a higher incidence of being small for gestational age (SGA). The infants had lower composite scores on Bayley-III and had more internalising and externalising behaviours on the CBCL. The mothers had more emotional problems on the DASS and higher scores on the EPDS. On multivariate analysis, SGA, greater internalising behaviours and higher EPDS scores remained statistically significant., Conclusions: A positive screen on the M-CHAT occurs more commonly in very preterm infants than those born at term. Internalising behaviours and maternal mental health are associated with a positive screen in the preterm cohort., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The prevalence of obesity among US children raises numerous health concerns. One pathway to reduce childhood obesity is by decreasing energy intake through the ingestion of fewer calories. Yet, food and beverage manufacturers often promote energy-dense items for children via varied health claims. Deceptive health claims are prohibited, and may be addressed through litigation or governmental regulatory efforts. While the amount of legal action against these potentially deceptive claims has increased, no comprehensive assessment has been conducted. This article, which analyzes litigation and governmental regulatory activities, considers key factors that may influence decisions to take legal action against potentially deceptive health claims on foods and beverages, including scientific support, forum selection, selection of plaintiffs, and potential public health impact.

Infections with monkeypox, cowpox and weaponized variola virus remain a threat to the increasingly unvaccinated human population, but little is known about their mechanisms of virulence and immune evasion. We now demonstrate that B22 proteins, encoded by the largest genes of these viruses, render human T cells unresponsive to stimulation of the T cell receptor by MHC-dependent antigen presentation or by MHC-independent stimulation. In contrast, stimuli that bypass TCR-signaling are not inhibited. In a non-human primate model of monkeypox, virus lacking the B22R homologue (MPXVΔ197) caused only mild disease with lower viremia and cutaneous pox lesions compared to wild type MPXV which caused high viremia, morbidity and mortality. Since MPXVΔ197-infected animals displayed accelerated T cell responses and less T cell dysregulation than MPXV US2003, we conclude that B22 family proteins cause viral virulence by suppressing T cell control of viral dissemination.

The problem of a single down-spin particle interacting with a Fermi sea of up-spin particles is of current interest in the field of cold atoms. The Hubbard model, appropriate to atoms in an optical lattice potential, is considered in parallel with a gas model. As the strength of an attractive short-range interaction is increased there is a crossover from 'polaron' behaviour, in which the Fermi sea is weakly perturbed, to 'molecule' behaviour in which the down-spin particle is bound to a single up-spin particle. It is shown that this is a smooth crossover, not a sharp transition as claimed by many authors.

Objective: To measure levels of parenting stress and postnatal depression in mothers of very preterm infants in comparison with mothers of infants born at term is the objective of this study. The study also aimed to explore factors associated with parenting stress in the mothers of the preterm infants., Methods: One hundred and five mothers who delivered 124 babies at ≤30 weeks gestation were enrolled together with 105 term mothers who delivered 120 babies. At one year of age (corrected for prematurity for the preterm cohort), the mothers completed the Parenting Stress Index Short Form (PSI), the Edinburgh Postnatal Depression Scale (EPDS) and the Short Temperament Scale for Toddlers. The infants had neurodevelopmental assessment. The preterm and term groups were compared., Results: Questionnaires were completed by 101 of the preterm mothers and 98 of the term mothers. The mean PSI Total Stress score was significantly higher for the preterm mothers (70.28 vs 64.52, p = 0.022), with 19% of the preterm group and 9% of the term group having high scores (p = 0.038).There was no group difference on the EPDS or measures of temperament, with disability being greater in the preterm infants. For the preterm group, maternal depression and infant temperament were independent predictors of Total Stress scores on multivariate analysis., Conclusions: Parenting stress in mothers of preterm infants at one year of age is significantly greater than that found in mothers of term infants. For preterm mothers, symptoms of depression and infant temperament are independent risk factors for higher levels of parenting stress., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Mothers of preterm infants during the first year of life may experience stresses greater that those found in mothers of term infants. The aim of the study was to determine the levels of parenting stress and psychological well-being in mothers of very preterm babies in comparison to a control group of term mothers., Methods: One hundred and five mothers who delivered 124 babies at ≤30weeks gestation were recruited together with 105 mothers who delivered 120 babies at term. At 4months of age (corrected for prematurity for the preterm babies), the mothers completed the Parenting Stress Index Short Form, the Edinburgh Postnatal Depression Scale (EPDS), the Dyadic Adjustment Scale (DAS) and the Short Temperament Scale for Infants (STSI). The preterm and term groups were compared., Results: Questionnaires were returned from 86 of the preterm mothers and 97 of the term mothers. The mean Total Stress score for the preterm and term groups was 67.0 and 63.79 respectively (P=0.32) with 17% of the preterm and 9% of the term group having high scores (P=0.135). There were no differences of the EPDS and the DAS between the groups. The temperament of the preterm infants was similar to the term infants. For both groups, scores on the EPDS, DAS and the STSI were independent predictors of Total Stress scores on multiple regression analysis., Conclusion: Parenting stress in mothers of preterm infants during early infancy does not appear to be greater than that in mothers of infants born at term. For both groups of mothers, depression symptoms, marital satisfaction and infant temperament were independent risk factors for high levels of parenting stress., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Holes in a Mott insulator are represented by spinless fermions in the fermion-boson model introduced by Edwards. Although the physically interesting regime is for low to moderate fermion density, the model has interesting properties over the whole density range. It has previously been studied at half-filling in the one-dimensional (1D) case by numerical methods, in particular using exact diagonalization and the density matrix renormalization group (DMRG). In the present study the one-particle Green's function is calculated analytically by means of a decoupling scheme for the equations of motion, valid for arbitrary density in 1D, 2D and 3D with fairly large boson energy and zero boson relaxation parameter. The Green's function is used to compute some ground state properties, and the one-fermion spectral function, for fermion densities n = 0.1, 0.5 and 0.9 in the 1D case. The results are generally in good agreement with numerical results obtained using the DMRG and dynamical DMRG, and new light is shed on the nature of the ground state at different fillings. The Green's function approximation is sufficiently successful in 1D to justify future application to the 2D and 3D cases.

Giant magnetoresistance (GMR) arises from differential scattering of the majority and minority spin electrons by a ferromagnet (FM) so that the resistance of a heterostructure depends on the relative magnetic orientation of the FM layers within it separated by nonmagnetic spacers. Here, we show that highly nonequilibrium spin accumulation in metallic heterostructures results in a current-dependent nonlinear GMR which is not predicted within the present understanding of GMR. The behavior can be explained by allowing the scattering asymmetries in an ultrathin FM layer to be current dependent.

Cowpox virus encodes an extensive array of putative immunomodulatory proteins, likely contributing to its wide host range, which includes zoonotic infections in humans. Unlike Vaccinia virus, cowpox virus prevents stimulation of CD8(+) T cells, a block that correlated with retention of MHC class I in the endoplasmic reticulum by the cowpox virus protein CPXV203. However, deletion of CPXV203 did not restore MHC class I transport or T cell stimulation. Here, we demonstrate the contribution of an additional viral protein, CPXV12, which interferes with MHC class I/peptide complex formation by inhibiting peptide translocation by the transporter associated with antigen processing (TAP). Importantly, human and mouse MHC class I transport and T cell stimulation was restored upon deletion of both CPXV12 and CPXV203, suggesting that these unrelated proteins independently mediate T cell evasion in multiple hosts. CPXV12 is a truncated version of a putative NK cell ligand, indicating that poxviral gene fragments can encode new, unexpected functions.

An extended Landau-Lifshitz-Gilbert (LLG) equation is introduced to describe the dynamics of inhomogeneous magnetization in a current-carrying wire. The coefficients of all the terms in this equation are calculated quantum-mechanically for a simple model which includes impurity scattering. This is done by comparing the energies and lifetimes of a spin wave calculated from the LLG equation and from the explicit model. Two terms are of particular importance since they describe non-adiabatic spin-transfer torque and damping processes which do not rely on spin-orbit coupling. It is shown that these terms may have a significant influence on the velocity of a current-driven domain wall and they become dominant in the case of a narrow wall.

We investigate charge transport within some background medium by means of an effective lattice model with a novel form of fermion-boson coupling. The bosons describe fluctuations of a correlated background. By analyzing ground state and spectral properties of this transport model, we show how a metal-insulator quantum phase transition can occur for the half-filled band case. We discuss the evolution of a mass-asymmetric band structure in the insulating phase and establish connections to the Mott and Peierls transition scenarios.

Twin-twin transfusion syndrome (TTTS) is a severe complication of twin pregnancies with high risk for perinatal mortality and long-term morbidity. This cross-sectional cohort study aimed to determine parenting stress and psychosocial health in mothers with a pregnancy complicated by TTTS that had been managed with laser ablation of communicating placental vessels. Questionnaires were sent to the mothers for completion: Parenting Stress Index (PSI), Edinburgh Postnatal Depression Scale (EPDS) and a semi-structured questionnaire related to mental health problems and support received from health professionals. Thirty-seven mothers were sent questionnaires with 32 being returned. The results showed that 47% of women had total scores equal to or greater than the 85th percentile on the PSI, which is considered abnormally high. Twenty-six per cent of mothers had evidence of depression on the EPDS. Mothers of children with prolonged medical conditions or neurological problems had significantly higher scores (p =.011). Parenting stress was not associated with high scores on the EPDS. Medical and midwifery staff were considered to provide high levels of support, with social work providing none or low levels of support. In conclusion, women whose TTTS pregnancy was managed by laser surgery have high levels of parenting stress. As the results showed that parenting stress cannot be predicted at the time of hospitalization, it is suggested that more support should be provided in hospital with further follow-up after discharge.

We study the interplay of collective dynamics and damping in the presence of correlations and bosonic fluctuations within the framework of a newly proposed model, which captures the principal transport mechanisms that apply to a variety of physical systems. We establish close connections to the transport of lattice and spin polarons, or the dynamics of a particle coupled to a bath. We analyze the model by exactly calculating the optical conductivity, Drude weight, spectral functions, ground state dispersion and particle-boson correlation functions for a 1D infinite system.

Splenic injury following colonoscopy is extremely rare. We report a 75-year-old woman and a 35-year-old woman who presented to the emergency room with left upper quadrant and left shoulder pain following colonoscopy. Both patients were diagnosed by computed tomography (CT) with splenic injuries and hemoperitoneum. One patient was successfully managed conservatively, and one patient needed emergent open splenectomy. The possibility of splenic injury should be considered in post-colonoscopy patients with left upper quadrant or left shoulder pain.

Chronic beryllium disease is a lung disorder caused by beryllium exposure in the workplace and is characterized by granulomatous inflammation and the accumulation of beryllium-specific, HLA-DP2-restricted CD4+ T lymphocytes in the lung that proliferate and secrete Th1-type cytokines. To characterize the interaction among HLA-DP2, beryllium, and CD4+ T cells, we constructed rHLA-DP2 and rHLA-DP4 molecules consisting of the alpha-1 and beta-1 domains of the HLA-DP molecules genetically linked into single polypeptide chains. Peptide binding to rHLA-DP2 and rHLA-DP4 was consistent with previously published peptide-binding motifs for these MHC class II molecules, with peptide binding dominated by aromatic residues in the P1 pocket. 9Be nuclear magnetic resonance spectroscopy showed that beryllium binds to the HLA-DP2-derived molecule, with no binding to the HLA-DP4 molecule that differs from DP2 by four amino acid residues. Using beryllium-specific CD4+ T cell lines derived from the lungs of chronic beryllium disease patients, beryllium presentation to those cells was independent of Ag processing because fixed APCs were capable of presenting BeSO4 and inducing T cell proliferation. Exposure of beryllium-specific CD4+ T cells to BeSO4 -pulsed, plate-bound rHLA-DP2 molecules induced IFN-gamma secretion. In addition, pretreatment of beryllium-specific CD4+ T cells with BeSO4-pulsed, plate-bound HLA-DP2 blocked proliferation and IL-2 secretion upon re-exposure to beryllium presented by APCs. Thus, the rHLA-DP2 molecules described herein provide a template for engineering variants that retain the ability to tolerize pathogenic CD4+ T cells, but do so in the absence of the beryllium Ag.

Chronic beryllium disease (CBD) is characterized pathologically by granulomatous inflammation in the lung, composed of a large core of epithelioid cells surrounded by a dense shell of CD4+ T cells. Using beryllium-specific CD4+ T cell lines derived from the bronchoalveolar lavage (BAL) fluid of CBD patients, we show that purified CD4+ T cells produced significant amounts of IFN-gamma and TNF-alpha upon exposure to beryllium in the absence of antigen-presenting cells (APC). However, unlike BAL T cells stimulated by beryllium in the presence of APC, self-presentation by BAL T cells did not induce detectable IL-2 production, and in its absence these activated T cells die from programmed cell death. Resting BAL CD4+ T cells constitutively express high levels of HLA-DP, lymphocyte function-associated antigen 1 (LFA-1) and ICAM-3. When stimulated with beryllium/APC, the adhesion molecule ICAM-1 was up-regulated, as well as several costimulation molecules including CD28, OX-40 (CD134), 4-1-BB (CD137) and B7-1 (CD80). Notably, CD28 was not up-regulated during self-presentation by BAL T cells, and these cells do not express OX-40L, suggesting that lack of appropriate costimulation was responsible for programmed cell death observed upon beryllium self-presentation. Restricting anti-MHC class II mAb completely eliminated beryllium-induced T cell proliferation during self-presentation and significantly reduced IFN-gamma and TNF-alpha production. Our data demonstrate for the first time that self-presentation by BAL T cells in response to beryllium can occur ex vivo, in the absence of professional APC, with a specific dependence on T cell-expressed MHC class II molecules and exogenous IL-2 for survival.

We show that a strongly renormalized band of polaronic quasiparticle excitations is induced at the Fermi level of an interacting many-electron system on increasing the coupling of the electrons to local phonons. We give results for the local density of states at zero temperature both for the electrons and phonons. The polaronic quasiparticles satisfy Luttinger's theorem for all regimes considered, and their dispersion shows a kink similar to that observed experimentally in copper oxides. Our calculations are based on the dynamical mean field theory and the numerical renormalization group for the hole-doped Holstein-Hubbard model and large on-site repulsion.