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There is a critical need to understand mechanisms of resistance and to develop combinatorial strategies to improve responses to checkpoint blockade immunotherapy (CBI). Here, we uncover a novel mechanism by which the human papillomavirus (HPV) inhibits the activity of CBI in head and neck squamous cell carcinoma (HNSCC). Using orthotopic HNSCC models, we show that radiation combined with anti-PD-L1 immunotherapy significantly enhanced local control, CD8+ memory T cells, and induced preferential T-cell homing via modulation of vascular endothelial cells. However, the HPV E5 oncoprotein suppressed immune responses by downregulating expression of major histocompatibility complex and interfering with antigen presentation in murine models and patient tumors. Furthermore, tumors expressing HPV E5 were rendered entirely resistant to anti-PD-L1 immunotherapy, and patients with high expression of HPV16 E5 had worse survival. The antiviral E5 inhibitor rimantadine demonstrated remarkable single-agent antitumor activity. This is the first report that describes HPV E5 as a mediator of resistance to anti-PD-1/PD-L1 immunotherapy and demonstrates the antitumor activity of rimantadine. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV-mediated immunosuppression, which can be exploited to improve response rates to checkpoint blockade. SIGNIFICANCE: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/4/732/F1.large.jpg.

Abstract Aim The pulmonary artery catheter (PAC)‐derived cardiac power index (CPI) has been found of prognostic value in cardiogenic shock (CS) patients. The original CPI equation included the right atrial pressure (RAP), accounting for heart filling pressure as a determinant of systolic myocardial work, but this term was subsequently omitted. We hypothesized that the original CPI formula (CPIRAP) is superior to current CPI for risk stratification in CS. Methods and results A single‐centre cohort of 80 consecutive Society for Cardiovascular Angiography and Interventions (SCAI) B‐D CS patients with available PAC records was included. Overall in‐hospital mortality was 21.3%. Results showed CPIRAP to be the strongest haemodynamic predictor of in‐hospital death (padj = 0.038), outperforming CPI [area under the receiver operating characteristic (ROC) curves: 0.726 and 0.673, P‐for‐difference = 0.025]. When the population was stratified according to the identified CPIRAP (0.28 W/m2) and accepted CPI (0.32 W/m2) thresholds, the cohort with discordant indexes (low CPIRAP and high CPI) comprised a group of 13 patients featuring a congested phenotype with frequent right ventricle or biventricular involvement. In this group, in‐hospital mortality was high (30.8%) similar to those with concordant low CPI and CPIRAP. Conclusion Incorporating RAP in CPI calculation (CPIRAP) improves the prognostic yield in patients with CS SCAI B‐D. A cut‐off of 0.28 W/m2 identifies patients at higher risk of in‐hospital mortality. The improved prognostic value of CPIRAP may derive from identification of patients with more intravascular congestion who may experience substantial in‐hospital mortality, uncaptured by the commonly used CPI equation.

Abstract Background Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (> 200 base pairs) on the promotor region of the fragile X messenger ribonucleoprotein 1 gene (FMR1). This leads to the deficiency or absence of the encoded protein, fragile X messenger ribonucleoprotein 1 (FMRP). FMRP has a central role in the translation of mRNAs involved in synaptic connections and plasticity. Recent studies have demonstrated the benefit of therapeutics focused on reactivation of the FMR1 locus towards improving key clinical phenotypes via restoration of FMRP and ultimately disease modification. A key step in future studies directed towards this effort is the establishment of proof of concept (POC) for FMRP reactivation in individuals with FXS. For this, it is key to determine the feasibility of repeated collection of tissues or fluids to measure FMR1 mRNA and FMRP. Methods Individuals, ages 3 to 22 years of age, with FXS and those who were typically developing participated in this single-site pilot clinical biomarker study. The repeated collection of hair follicles was compared with the collection of blood and buccal swabs for detection of FMR1 mRNA and FMRP and related molecules. Results There were n = 15 participants, of whom 10 had a diagnosis of FXS (7.0 ± 3.56 years) and 5 were typically developing (8.2 ± 2.77 years). Absolute levels of FMRP and FMR1 mRNA were substantially higher in healthy participants compared to full mutation and mosaic FXS participants and lowest in the FXS boys. Measurement of FMR1 mRNA and FMRP levels by any method did not show any notable variation by collection location at home versus office across the various sample collection methodologies of hair follicle, blood sample, and buccal swab. Conclusion Findings demonstrated that repeated sampling of hair follicles in individuals with FXS, in both, home, and office settings, is feasible, repeatable, and can be used for measurement of FMR1 mRNA and FMRP in longitudinal studies.

ObjectivesWe validated a screening protocol in which thoracic ultrasound (TUS) acts as a first-line complementary imaging technique in selecting patients which may deserve a second-line low-dose high resolution computed tomography (HRCT) scan among a population of asymptomatic high-risk subjects for interstitial lung abnormalities (ILA) and lung cancer. Due to heavy environmental pollution burden, the district Tamburi of Taranto has been chosen as “case study” for this purpose.MethodsFrom July 2018 to October 2020, 677 patients aged between 45 and 65 year and who had been living in the Tamburi district of Taranto for at least 10 years were included in the study. After demographic, clinical and risk factor exposition data were collected, each participant underwent a complete TUS examination. These subjects were then asked to know if they agreed to perform a second-level examination by low-dose HRCT scan.ResultsOn a total of 167 subjects (24.7%) who agreed to undergo a second-level HRCT, 85 patients (50.9%) actually showed pleuro-pulmonary abnormalities. Interstitial abnormalities were detected in a total of 36 patients on HRCT scan. In particular, 34 participants presented subpleural ILAs, that were classified in the fibrotic subtype in 7 cases. The remaining 2 patients showed non-subpleural interstitial abnormalities. Subpleural nodules were observed in 46 patients. TUS showed an overall diagnostic accuracy of 88.6% in detecting pleuro-pulmonary abnormalities in comparison with HRCT scan, with a sensitivity of 95.3%, a specificity of 81.7%, a positive predictive value of 84.4% and a negative predictive value of 94.4%. The matched evaluation of specific pulmonary abnormalities on HRTC scan (i.e., interstitial abnormalities or pulmonary nodules) with determinate sonographic findings revealed a reduction in both TUS sensibility and specificity. Focusing TUS evaluation on the assessment of interstitial abnormalities, a thickened pleural line showed a sensitivity of 63.9% and a specificity of 69.5%, hypoechoic striae showed a sensitivity of 38.9% and a specificity of 90.1% and subpleural nodules showed a sensitivity of 58.3% and a specificity of 77.1%. Regarding to the assessment of subpleural nodules, TUS showed a sensitivity of 60.9% and a specificity of 81.0%. However, the combined employment of TUS examination and HRCT scans allowed to identify 34 patients with early subpleural ILA and to detect three suspicious pulmonary nodules (of which two were intraparenchymal and one was a large subpleural mass), which revealed to be lung cancers on further investigations.ConclusionA first-line TUS examination might aid the identification of subjects highly exposed to environmental pollution, who could benefit of a second-line low-dose HRCT scan to find early interstitial lung diseases as well as lung cancer.Protocol registration codePLEURO-SCREENING-V1.0_15 Feb, 17.

Classical T Tauri Stars (CTTSs) are highly variable stars that possess gas- and dust-rich disks from which planets form. Much of their variability is driven by mass accretion from the surrounding disk, a process that is still not entirely understood. A multiepoch optical spectral monitoring campaign of four CTTSs (TW Hya, RU Lup, BP Tau, and GM Aur) was conducted along with contemporaneous Hubble Space Telescope (HST) UV spectra and ground-based photometry in an effort to determine accretion characteristics and gauge variability in this sample. Using an accretion flow model, we find that the magnetospheric truncation radius varies between 2.5 and 5 R _⋆ across all of our observations. There is also significant variability in all emission lines studied, particularly H α , H β , and H γ . Using previously established relationships between line luminosity and accretion, we find that, on average, most lines reproduce accretion rates consistent with accretion shock modeling of HST spectra to within 0.5 dex. Looking at individual contemporaneous observations, however, these relationships are less accurate, suggesting that variability trends differ from the trends of the population and that these empirical relationships should be used with caution in studies of variability.

Tuberculous pericarditis (TBP) is an important cause of pericarditis worldwide while being infrequent in childhood, especially in low-TB-incidence countries. We report a case of TBP and provide a systematic review of the literature, conducted by searching PubMed, Scopus, and Cochrane to find cases of TBP in pediatric age published in the English language between the year 1990 and the time of the search. Of the 587 search results obtained, after screening and a backward citation search, 45 studies were selected to be included in this review, accounting for a total of 125 patients. The main signs and symptoms were fever, cough, weight loss, hepatomegaly, dyspnea, and increased jugular venous pressure or jugular vein turgor. A definitive diagnosis of TBP was made in 36 patients, either thanks to microbiological investigations, histological analysis, or both. First-line antitubercular treatment (ATT) was administered in nearly all cases, and 69 children underwent surgical procedures. Only six patients died, and only two died of TBP. TBP in childhood is relatively uncommon, even in high-TB-prevalence countries. Clinical manifestations, often suggestive of right-sided cardiac failure, are subtle, and diagnosis is challenging. TBP has an excellent prognosis in childhood; however, in a significant proportion of cases, invasive surgical procedures are necessary.

Pre-main-sequence disk accretion is pivotal for determining the final stellar properties and the early conditions for close-in planets. We aim to establish the impact of internal (stellar mass) and external (radiation field) parameters on the disk evolution in the Lagoon Nebula massive star-forming region. We employ simultaneous u , g , r , i , H α time-series photometry, archival infrared data, and high-precision K2 light curves to derive the stellar, disk, and accretion properties for 1012 Lagoon Nebula members. We estimate that of all young stars in the Lagoon Nebula, 34%–37% have inner disks traceable down to ∼12 μ m, while 38%–41% are actively accreting. We detect disks ∼1.5 times more frequently around G, K, and M stars than around higher-mass stars, which appear to deplete their inner disks on shorter timescales. We find tentative evidence for a faster disk evolution in the central regions of the Lagoon Nebula, where the bulk of the O/B population is located. Conversely, disks appear to last longer at the nebula outskirts, where the measured fraction of disk-bearing stars tends to exceed that of accreting and disk-free stars. The derived mass accretion rates show a nonuniform dependence on stellar mass between ∼0.2 and 5 M _⊙ . In addition, the typical accretion rates appear to differ across the Lagoon Nebula extension, with values twice lower in the core region than at its periphery. Finally, we detect tentative radial density gradients in the surface accretion shocks, leading to lags in the appearance of light curve brightness features as a function of wavelength that can amount to ∼7%–30% of the rotation period.

Epstein–Barr (EBV) is a human γ-herpesvirus that undergoes both a productive (lytic) cycle and a non-productive (latent) phase. The virus establishes enduring latent infection in B lymphocytes and productive infection in the oral mucosal epithelium. Like other herpesviruses, EBV expresses its genes in a coordinated pattern during acute infection. Unlike others, it replicates its DNA during latency to maintain the viral genome in an expanding pool of B lymphocytes, which are stimulated to divide upon infection. The reactivation from the latent state is associated with a productive gene expression pattern mediated by virus-encoded transcriptional activators BZLF-1 and BRLF-1. EBV is a highly transforming virus that contributes to the development of human lymphomas. Though viral vectors and mRNA platforms have been used to develop an EBV prophylactic vaccine, currently, there are no vaccines or antiviral drugs for the prophylaxis or treatment of EBV infection and EBV-associated cancers. Natural products and bioactive compounds are widely studied for their antiviral potential and capability to modulate intracellular signaling pathways. This review was intended to collect information on plant-derived products showing their antiviral activity against EBV and evaluate their feasibility as an alternative or adjuvant therapy against EBV infections and correlated oncogenesis in humans.

BackgroundPain management racial disparities exist, yet it is unclear whether disparities exist in pain management in advanced cancer.ObjectiveTo examine the effect of race on physicians' pain assessment and treatment in advanced lung cancer and the moderating effect of patient activation.DesignRandomized field experiment. Physicians consented to see two unannounced standardized patients (SPs) over 18 months. SPs portrayed 4 identical roles-a 62-year-old man with advanced lung cancer and uncontrolled pain-differing by race (black or white) and role (activated or typical). Activated SPs asked questions, interrupted when necessary, made requests, and expressed opinions.ParticipantsNinety-six primary care physicians (PCPs) and oncologists from small cities, and suburban and rural areas of New York, Indiana, and Michigan. Physicians' mean age was 52 years (SD = 27.17), 59% male, and 64% white.Main measuresOpioids prescribed (or not), total daily opioid doses (in oral morphine equivalents), guideline-concordant pain management, and pain assessment.Key resultsSPs completed 181 covertly audio-recorded visits that had complete data for the model covariates. Physicians detected SPs in 15% of visits. Physicians prescribed opioids in 71% of visits; 38% received guideline-concordant doses. Neither race nor activation was associated with total opioid dose or guideline-concordant pain management, and there were no interaction effects (p > 0.05). Activation, but not race, was associated with improved pain assessment (ẞ, 0.46, 95% CI 0.18, 0.74). In post hoc analyses, oncologists (but not PCPs) were less likely to prescribe opioids to black SPs (OR 0.24, 95% CI 0.07, 0.81).ConclusionsNeither race nor activation was associated with opioid prescribing; activation was associated with better pain assessment. In post hoc analyses, oncologists were less likely to prescribe opioids to black male SPs than white male SPs; PCPs had no racial disparities. In general, physicians may be under-prescribing opioids for cancer pain.Trial registrationNCT01501006.

The complete nucleotide sequence of the mitochondrial (mt) genome of the demersal zebra seabream Diplodus cervinus (Lowe, 1838) was determined for the first time. The double stranded circular molecule is 16,559 base pairs (bp) in length and encodes for the typical 37 metazoan mitochondrial genes, and 2 non-coding regions (D-loop and L-origin). The gene arrangement of the D. cervinus mt genome follows the usual one for fishes. The nucleotide sequences of the mt protein coding and ribosomal genes of D. cervinus mt genome were aligned with orthologous sequences from representatives of the Sparidae family and phylogenetic relationships were inferred. Maximum likelihood analyses placed D. cervinus as a sister species of Diplodus sargus (Linnaeus, 1758).

In this study, we investigated whether the difficulties in body motion (BM) perception may led to deficit in emotion recognition in Autism spectrum disorder (ASD). To this aim, individuals with high-functioning ASD were asked to recognise fearful, happy, and neutral BM depicted as static images or dynamic point-light and full-light displays. Results showed slower response times in participants with ASD only in recognising dynamic stimuli, but no group differences in accuracy. This suggests that i) a deficit in action chaining mechanism in ASD may prevent the recognition of dynamic BM automatically and rapidly, ii) individuals with ASD and high cognitive resources can develop alternative-but equally successful-strategies to recognise emotional body expressions. Implications for treatment are discussed, Author(s): Noemi Mazzoni [sup.1] , Paola Ricciardelli [sup.2] [sup.3] , Rossana Actis-Grosso [sup.2] [sup.3] , Paola Venuti [sup.1] Author Affiliations: (1) grid.11696.39, 0000 0004 1937 0351, OFDLab - Department of [...]

ABSTRACT Tumor suppressor p53 and its related proteins, p63 and p73, can be synthesized as multiple isoforms lacking part of the N- or C-terminal regions. Specifically, high expression of the ΔNp73α isoform is notoriously associated with various human malignancies characterized by poor prognosis. This isoform is also accumulated by oncogenic viruses, such as Epstein–Barr virus (EBV), as well as genus beta human papillomaviruses (HPV) that appear to be involved in carcinogenesis. To gain additional insight into ΔNp73α mechanisms, we have performed proteomics analyses using human keratinocytes transformed by the E6 and E7 proteins of the beta-HPV type 38 virus as an experimental model (38HK). We find that ΔNp73α associates with the E2F4/p130 repressor complex through a direct interaction with E2F4. This interaction is favored by the N-terminal truncation of p73 characteristic of ΔNp73 isoforms. Moreover, it is independent of the C-terminal splicing status, suggesting that it could represent a general feature of ΔNp73 isoforms (α, β, γ, δ, ε, ζ, θ, η, and η1). We show that the ΔNp73α-E2F4/p130 complex inhibits the expression of specific genes, including genes encoding for negative regulators of proliferation, both in 38HK and in HPV-negative cancer-derived cell lines. Such genes are not inhibited by E2F4/p130 in primary keratinocytes lacking ΔNp73α, indicating that the interaction with ΔNp73α rewires the E2F4 transcriptional program. In conclusion, we have identified and characterized a novel transcriptional regulatory complex with potential implications in oncogenesis. IMPORTANCE The TP53 gene is mutated in about 50% of human cancers. In contrast, the TP63 and TP73 genes are rarely mutated but rather expressed as ΔNp63 and ΔNp73 isoforms in a wide range of malignancies, where they act as p53 antagonists. Accumulation of ΔNp63 and ΔNp73, which is associated with chemoresistance, can result from infection by oncogenic viruses such as EBV or HPV. Our study focuses on the highly carcinogenic ΔNp73α isoform and uses a viral model of cellular transformation. We unveil a physical interaction between ΔNp73α and the E2F4/p130 complex involved in cell cycle control, which rewires the E2F4/p130 transcriptional program. Our work shows that ΔNp73 isoforms can establish interactions with proteins that do not bind to the TAp73α tumor suppressor. This situation is analogous to the gain-of-function interactions of p53 mutants supporting cellular proliferation.

Breast cancer (BC) is the second most common cause of brain metastasis onset in patients, with the cerebellum accounting for the 33% of cases. In the current study, using a 4T1 triple-negative mouse BC model, we revealed that an orally administered medicinal mushrooms (MM) blend, rich in β-glucans, played a direct and specific anti-cancer action on cerebellar metastases, also bettering locomotor performances. The neuroprotective effect of the MM blend plays through (i) a direct and specific inhibition of cerebellar metastatization pattern typical of TNBC (with an induced reduction of about 50% of metastases density) and (ii) the regulation of apoptosis and proliferation-related genes, as suggested by expression changes of specific molecular markers, i.e. PCNA, p53, Bcl2, BAX, CASP9, CASP3, Hsp70 and AIF. Therefore, inhibiting the metastatization process, triggering a significant apoptosis increase, and lessening cell proliferation, this MM supplement, employed as adjuvant treatment in association with conventional therapy, could represent a promising approach, in the field of Integrative Oncology, for patients’ management in both prevention and treatment of brain metastases from BC.