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• An MSM was diagnosed with monkeypox (MPX) and concurrent STI and STEIs. • Sexual intercourse might be the predominant way of transmission of MPX. • Physicians should be aware of MPX among individuals with a previous history of STIs. • Presence of a concurrent STI should not rule out MPX infection and vice versa. • Anoscopy might be helpful in revealing unnoticed MPX lesion. [ABSTRACT FROM AUTHOR]

The concept of crystal collimation exploits the peculiar properties of crystalline materials to deflect high-energy beam particles at angles orders of magnitude larger than what can be achieved with scattering by conventional materials used as primary collimators. This innovative technique is planned to be used to improve the collimation efficiency with heavy-ion beams at the Large Hadron Collider (LHC) and its High-Luminosity upgrade (HL-LHC). The unprecedented proton-equivalent energy range of up to 7 TeV makes this technique particularly challenging due to the small angular acceptance of the crystal channeling process. This paper reviews the recent campaign of measurements performed with 6.8 TeV proton beams at the LHC to characterize the latest generation of crystal collimator devices installed in the machine, in preparation for the deployment in the upcoming heavy-ion runs. [ABSTRACT FROM AUTHOR]

Purpose To investigate the applicability of the formalism described in BJR supplement n.25 for Flattening Filter Free (FFF) beams in determining the zero-field tissue maximum ratio (TMR) for an independent calculation method of Percentage Depth Doses (PDDs) and relative dose factors (RDFs) at different experimental setups. Methods Experimental PDDs for field size from 40 × 40 cm 2 to 2 × 2 cm 2 with Source Surface Distance (SSD) 100 cm were acquired. The normalized peak scatter factor for each square field was obtained by fitting experimental RDFs in water and collimator factors (CFs) in air. Maximum log-likelihood methods were used to extract fit parameters in competing models and the Bayesian Information Criterion was used to select the best one. In different experimental setups additional RDFs and TPR 10 20 s for field sizes other than reference field were measured and Monte Carlo simulations of PDDs at SSD 80 cm were carried out to validate the results. PDD agreements were evaluated by gamma analysis. Results The BJR formalism allowed to predict the PDDs obtained with MC within 2%/2 mm at SSD 80 cm from 100% down to 50% of the maximum dose. The agreement between experimental TPR 10 20 s and RDFs values at SSD = 90 cm and BJR calculations were within 1% for field sizes greater than 5 × 5 cm 2 while it was within 3% for fields down to 2 × 2 cm 2 . Conclusions BJR formalism can be used for FFF beams to predict PDD and RDF at different SSDs and can be used for independent MU calculations. [ABSTRACT FROM AUTHOR]

The nuclear DNA sensor IFI16, a member of PYHIN family of proteins, was previously studied for its role in cell cycle regulation, tumor suppression, apoptosis and DNA damage signaling. Autoantibodies against IFI16 are prevalent in the sera of patients with systemic autoimmunity, thus depicting physiological significance as an autoantigen. At present, the nuclear IFI16 protein has been thoroughly investigated for its role as an innate immune sensor involved in inflammasome signaling and viral restriction. While the sub-cellular localization of IFI16 during such events has been known, very little knowledge about its presence and significance in the extracellular space is available. Recently our group has discovered the presence of circulating IFI16 in the sera from systemic autoimmune patients indicating that in this setting it may be mislocalized form its nuclear site and secreted in the extracellular milieu. In this review, we will discuss the leakage of endogenous IFI16 that has been experimentally proved using in vivo and in vitro models. Also we will comment on the significance of mislocalized inflammasome components in the extracellular space and how it can be responsible for chronic inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Production of extended-spectrum β-lactamases (ESBLs) is the principal mechanism of resistance to oxyimino-cephalosporins evolved by members of the family Enterobacteriaceae. Among the several ESBLs emerged among clinical pathogens, the CTX-M-type enzymes have proved the most successful in terms of promiscuity and diffusion in different epidemiological settings, where they have largely replaced and outnumbered other types of ESBLs. Originated by the capture and mobilization of chromosomal β-lactamase genes of strains of Kluyvera species, the bla CTX-M genes have become associated with a variety of mobile genetic elements that have mediated rapid and efficient inter-replicon and cell-to-cell dissemination involving highly successful enterobacterial lineages (e.g. Escherichia coli ST131 and ST405, or Klebsiella pneumoniae CC11 and ST147) to yield high-risk multiresistant clones that have spread on a global scale. The CTX-Mβ-lactamase lineage exhibits a striking plasticity, with a large number of allelic variants belonging in several sublineages, which can be associated with functional heterogeneity of clinical relevance. This review article provides an update on CTX-M-type ESBLs, with focus on structural and functional diversity, epidemiology and clinical significance. [Copyright &y& Elsevier]

Abstract: The Interferon-inducible gene, IFI16 has been implicated in the control of cell growth, apoptosis, angiogenesis and immunomodulation. In a previous study we demonstrated that restoring levels of IFI16 in a head and neck squamous cell carcinoma (HNSCC)-derived cell line, HNO136, reduced its growth in vitro accompanied by a marked increase in doxorubicin-induced apoptosis. To evaluate the ability of IFI16 to inhibit in vivo tumorigenesis of HNO136 cells and to characterize the molecular mechanisms responsible for its anti-tumor activity, IFI16 expression on cell growth was evaluated by an in vivo tumorigenicity assay. After excision, tumors were subjected to morphometric and immunohistochemical analyses with markers of apoptosis, angiogenesis, and inflammation. Restoring IFI16 expression significantly reduced the in vivo tumorigenesis of HNO136, decreased tumor vascularization and increased areas of tumor necrosis. Further analysis revealed that IFI16 expression triggered apoptosis of tumor cells, as evaluated using TUNEL assay. Finally, restoring IFI16 protein to HNO136 cells increased CD45+ inflammatory cell infiltration of the tumor burden, predominantly consisting of CD68/CD14 positive macrophages. In accordance with our previous in vitro experiments, this study demonstrates for the first time that IFI16 exerts in vivo anti-tumoral activity by promoting apoptosis of tumor cells, by inhibiting neo-vascularisation, and by increasing the recruitment of macrophages through the release of chemotactic factors. [Copyright &y& Elsevier]

Abstract: Keratinocytes, the target cell of human papillomavirus (HPV) infection, can produce numerous cytokines and pro-inflammatory molecules which are important for the generation of an effective immune response. How this biological response, which involves the tumor stroma, is affected by the HPV oncoproteins within the epithelial cell itself is not clear. Here it is shown that oncoproteins of different HPV genotypes (alpha- versus beta-HPV genus) alter the expression of pro-inflammatory molecules in early passage primary human keratinocytes and the immortalized cell line HaCaT. HPV5 E6/E7 oncoproteins significantly induced interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) expression. By contrast, the same molecules were down-regulated or not modulated in HPV16 E6/E7 transduced keratinocytes. Interestingly, HPV38 oncoproteins expression resulted in a lower induction of pro-inflammatory molecules, resembling the behavior displayed by the mucosal carcinogenic HPV16. Finally, inducible nitric oxide synthase (iNOS) expression levels and nitric oxide (NO) production were induced at similar levels by all the HPV genotypes tested. These results further emphasize the different biological activities among HPV genotypes, and offer new insights into HPV-associated skin diseases. [Copyright &y& Elsevier]

Purpose Radioembolization (RE) with 90 Y-microspheres is a well-established treatment modality for treating liver malignancies. At a time of increasing evidence for dose–effect relationships in RE with 90 Y microspheres [1,2] , the general consensus is that there is an urgent need for accurate dosimetry in patients undergoing RE treatment. This work aimed at estimating absorbed doses to lesions and normal liver in a novel anthropomorphic set-up. Methods AbdoMan is a 3D-printed phantom provided with a fillable liver section and multiple inserts for lesion representation. A SPECT/CT Symbia Intevo provided with the proprietary xSPECT quantitative software was used to image the phantom according to the acquisition protocol currently used for RE patients. Specific regions of interest (ROIs) were drawn on MIM 6.1.7 system. A homemade tool was developed in MATLAB for image analysis and dose calculation based on two methods: I) convolution kernel and II) local deposition method. The accuracy of the two different dosimetric methods was evaluated by comparing dose-rate volume histograms (DrVHs). Moreover, γ -index was used to compare the dose distributions obtained by the two activity-to-dose methods. Results Differences calculated by the 3D γ -index are within 2%-2 mm for all AbdoMan inserts. The dose-kernel results in a γ  < 1. The deposition method provided a poorest γ as well as several image artefacts. In particular, an apparent over-dosage (about 25%) was observed in inserts with larger diameter, most likely due to spill-in and spill-out phenomena. The DrVHs for considered ROIs are within 2%-2 mm for both methods. Conclusions In RE treatment planning the dose-kernel method proved to be more accurate with respect to deposition method based on full 3D dose distributions. [ABSTRACT FROM AUTHOR]

Purpose Radioembolization (RE) with 90 Y-microspheres has gained widespread acceptance as a safe and effective technique for treating liver malignancies. Accurate quantification in RE is a key step in treatment planning optimization and it is becoming a pressing issue in the light of the Directive 2013/59/EURATOM, stating that individual dose planning must be enforced in legislation by EU member states by February 2018. The aim of this study was to develop a SPECT/CT imaging protocol for quantitative imaging optimization in RE based on a novel anthropomorphic 3D-printed phantom. Methods and materials A SPECT/CT system provided with a novel software for imaging quantification was used to assess the quantitative accuracy of 99m Tc-MAA SPECT imaging for treatment planning in RE. Gamma camera calibration factors and recovery coefficients were determined performing preliminary SPECT/CT acquisitions of a homogeneous and a NEMA/IEC phantom, respectively. The quantification procedure was then validated using a 3D-printed anthropomorphic phantom provided with a fillable liver section and multiple inserts. Raw data reconstruction was performed using two independent software: i) the built-in xSPECT package, using both the Ordered Subset Expectation–Maximization (OSEM) and the Ordered Subset Conjugated Gradient (OSCG) algorithm; ii) the commercially available QSPECT software based on OSEM method. All reconstructed images were manually fused and appropriate regions of interest (ROIs) were drawn on the MIM 6.1.7 system. Results The measured activity concentration is consistent within 3% with the expected activity concentration values. This is in keeping with the overall accuracy ( < 10%) stated by the manufacturer. No substantial differences were reported between xSPECT with OSCG or OSEM in terms of relative activity. However, a 20% difference was found between ROIs extracted from images reconstructed with xSPECT and QSPECT using OSEM. Several artifacts were visible in the QSPECT reconstruction, likely due to the limited area used for attenuation and scatter corrections within the software. Conclusions The investigated protocol based on the innovative xSPECT tool allows an accurate absolute quantification within 3%. QSPECT software provides the poorest results with several artifacts as well as intrinsic dishomogeneities. [ABSTRACT FROM AUTHOR]

Background: Correlating human papillomavirus (HPV) type with the clinical and histopathological features of skin lesions (from genital and nongenital sites) can present a diagnostic challenge.Objective: In this study, HPV infection patterns were correlated with pathology and clinical presentation in lesional and nonlesional body sites from a young patient with a primary T-cell immunodeficiency.Methods: HPV infection was evaluated at both DNA and protein levels by polymerase chain reaction and immunohistochemistry.Results: The patient's genital lesions were caused exclusively by α-genotypes (high-risk type HPV-51 in the anal and low-risk type HPV-72 in the penile condylomas). The opposite was true for the skin lesions, which were infected by β-genotypes alone (HPV-8 and HPV-24). HPV-24 was the predominant type in terms of viral load, and the only one found in productive areas of infection. The patient had already developed high-grade dysplasia in the anal condyloma-like lesions, and showed areas of early-stage dysplasia in the lesions caused by the β-genotype HPV-24.Limitations: The basic origin of the immunodeficiency is not yet defined.Conclusion: These findings provide proof of principle that both α- and β-genotypes can cause overt dysplastic lesions when immunosurveillance is lost, which is not restricted to epidermodysplasia verruciformis. [ABSTRACT FROM AUTHOR]

Epidermodysplasia verruciformis (EV) is a rare disease, characterized by cutaneous warts and associated with a strong predisposition to β-genus human papillomavirus (HPV). Earlier studies reported high copy numbers of HPV-DNA in nearly all skin tumors from EV patients, but neither HPV replication status in non-lesional skin nor anti-HPV seroreactivity in these patients have been reported yet. We therefore performed a comprehensive viral load analysis for the more common β-HPV types on skin samples and plucked eyebrow hairs from four EV patients treated at our dermatology department. The results clearly demonstrate that they carry a multiplicity (up to eighteen types) of β-HPV genotypes in both skin sites. Worthy of note, a high intrapatient concordance for specific types between hair bulbs and skin biopsies was observed and the same β-PV profile was maintained over time. Viral load analysis revealed a load range between less than one HPV-DNA copy per 100 cells to more than 400 HPV-DNA copies per cell in both eyebrow hairs and skin proliferative lesions. Evaluation of seroreactivity to β-HPV types in the four EV patients revealed that antibodies against the 16 β-HPV were significantly more prevalent and showed higher titers than in the controls.Journal of Investigative Dermatology (2009) 129, 1026–1034; doi:10.1038/jid.2008.317; published online 16 October 2008 [ABSTRACT FROM AUTHOR]

Abstract: A remarkable increase in Proteus mirabilis strains producing acquired AmpC-type β-lactamases (CBLs) has been observed at Ospedale di Circolo e Fondazione Macchi (Varese, Italy) over the last few years. The epidemiology and treatment outcome of infections associated with this unprecedented spread are reported. From 2004–2006, 2070 P. mirabilis isolates were investigated. Extended-spectrum β-lactamases (ESBLs) and CBL resistance determinants were identified by gene amplification and direct sequencing. Clonal relatedness was evaluated by macrorestriction analysis. Overall, 43 CBL-positive isolates were obtained from hospitalised (n =22) and non-hospitalised (n =21) patients (median age 78.8 years). The prevalence of CBL-positive isolates increased from 0.3% in 2004 to 4.6% in 2006, whereas that of ESBL-positive isolates remained constant (ca. 10%). CBL-positive isolates were multidrug-resistant and carried the CMY-16 determinant. All but two isolates were genetically identical or closely related. Retrospective analysis of clinical records revealed that the majority of CMY-16-positive isolates were associated with urinary tract infections. Treatment with amikacin or carbapenems was consistently effective, whereas piperacillin/tazobactam produced a clinical response in seven of nine cases. This is the first report of a rapid spread of CBL-positive P. mirabilis strains endowed with remarkable antimicrobial resistance. Practical methods for CBL detection are needed for the appropriate management of related infections. [Copyright &y& Elsevier]

Klebsiella pneumoniae strain KPB-1 was isolated in early 2011 from the pleural fluid of an inpatient admitted at an Italian hospital. It was characterized to produce the KPC-3 carbapenemase and to belong to sequence type 512, a derivative of sequence type 258 clade II characterized by the cps-2 gene cluster. The K-antigen of K. pneumoniae KPB-1 was purified and its structure determined by using GLC-MS of appropriate carbohydrate derivatives and 1D and 2D NMR spectroscopy of the native polysaccharide. All the collected data demonstrated the following repeating unit for the K. pneumoniae KPB-1 capsular polysaccharide: Unlabelled Image The reactions catalysed by each glycosyltransferase in the cps-2 gene cluster were assigned on the basis of structural homology with other Klebsiella K antigens. Unlabelled Image • The CPS produced by a K. pneumoniae ST512 strain was characterized for the first time. • It consists of a branched hexasaccharide repeating unit rich in rhamnose. • Glycosyltransferases functions in the CPS gene cluster were identified. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae strain KK207-2 was isolated in 2010 from a bloodstream infection of an inpatient at an Italian hospital. It was previously found to produce the KPC-2 carbapenemase and to belong to clade 1 of sequence type 258. Genotyping of the conserved wzi and wzc genes from strain KK207-2 yielded contrasting results: the wzc -based method assigned the cps 207–2 to a new K-type, while the wzi -based method assigned it to the known K41 K-type. In order to resolve this contradiction, the capsular polysaccharide of K. pneumoniae KK207-2 was purified and its structure determined by using GLC-MS of appropriate carbohydrate derivatives, ESI-MS of both partial hydrolysis and Smith degradation derived oligosaccharides, and NMR spectroscopy of oligosaccharides, and the lithium degraded, native and de- O -acetylated polysaccharide. All the collected data demonstrated the following repeating unit for the K. pneumoniae KK207-2 capsular polysaccharide: Unlabelled Image The polysaccharide contains about 0.60 acetyl groups per repeating unit on C6 of the Gal residue. The reactions catalyzed by each glycosyltransferase in the cps KK207-2 gene cluster were assigned on the basis of structural homology with other Klebsiella K antigens. [ABSTRACT FROM AUTHOR]

The current SARS-CoV-2 pandemic, along with the likelihood that new coronavirus strains will appear in the nearby future, highlights the urgent need to develop new effective antiviral agents. In this scenario, emerging host-targeting antivirals (HTAs), which act on host-cell factors essential for viral replication, are a promising class of antiviral compounds. Here we show that a new class of HTAs targeting peptidylarginine deiminases (PADs), a family of calcium-dependent enzymes catalyzing protein citrullination, is endowed with a potent inhibitory activity against human beta-coronaviruses (HCoVs). Specifically, we show that infection of human fetal lung fibroblasts with HCoV-OC43 leads to enhanced protein citrullination through transcriptional activation of PAD4, and that inhibition of PAD4-mediated citrullination with either of the two pan-PAD inhibitors Cl-A and BB-Cl or the PAD4-specific inhibitor GSK199 curbs HCoV-OC43 replication. Furthermore, we show that either Cl-A or BB-Cl treatment of African green monkey kidney Vero-E6 cells, a widely used cell system to study beta-CoV replication, potently suppresses HCoV-OC43 and SARS-CoV-2 replication. Overall, our results demonstrate the potential efficacy of PAD inhibitors, in suppressing HCoV infection, which may provide the rationale for the repurposing of this class of inhibitors for the treatment of COVID-19 patients. • Beta-coronavirus replication induces peptidyl-arginine deiminase (PAD)-mediated citrullination in vitro. • The PAD inhibitors Cl-amidine and BB-Cl-amidine strongly impair HCoV-OC43 and SARS-CoV-2 replication in vitro. • PAD inhibitors may be repurposed for treating HCoV-associated infections. [ABSTRACT FROM AUTHOR]

Purpose: One of the worst radiation-induced acute effects in treating head-and-neck (HN) cancer is grade 3 or higher acute (oral and pharyngeal) mucosal toxicity (AMT), caused by the killing/depletion of mucosa cells. Here we aim to testing a predictive model of the AMT in HN cancer patients receiving different radiotherapy schedules. Methods and Materials: Various radiotherapeutic schedules have been reviewed and classified as tolerable or intolerable based on AMT severity. A modified normal tissue complication probability (NTCP) model has been investigated to describe AMT data in radiotherapy regimens, both conventional and altered in dose and overall treatment time (OTT). We tested the hypothesis that such a model could also be applied to identify intolerable treatment and to predict AMT. This AMT NTCP model has been compared with other published predictive models to identify schedules that are either tolerable or intolerable. The area under the curve (AUC) was calculated for all models, assuming treatment tolerance as the gold standard. The correlation between AMT and the predicted toxicity rate was assessed by a Pearson correlation test. Results: The AMT NTCP model was able to distinguish between acceptable and intolerable schedules among the data available for the study (AUC = 0.84, 95% confidence interval = 0.75-0.92). In the equivalent dose at 2 Gy/fraction (EQD2) vs OTT space, the proposed model shows a trend similar to that of models proposed by other authors, but was superior in detecting some intolerable schedules. Moreover, it was able to predict the incidence of ≥G3 AMT. Conclusion: The proposed model is able to predict ≥G3 AMT after HN cancer radiotherapy, and could be useful for designing altered/hypofractionated schedules to reduce the incidence of AMT. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the lack of EVER2 protein in Epidermodysplasia Verruciformis (EV) patients with skin cancer who had previous unreported homozygous genetic deletions in the EVER2 gene.

Abstract: Cone-beam X-ray volumetric imaging in the treatment room, allows online correction of set-up errors and offline assessment of residual set-up errors and organ motion. In this study the registration algorithm of the X-ray volume imaging software (XVI, Elekta, Crawley, United Kingdom), which manages a commercial cone-beam computed tomography (CBCT)–based positioning system, has been tested using a homemade and an anthropomorphic phantom to: (1) assess its performance in detecting known translational and rotational set-up errors and (2) transfer the transformation matrix of its registrations into a commercial treatment planning system (TPS) for offline organ motion analysis. Furthermore, CBCT dose index has been measured for a particular site (prostate: 120 kV, 1028.8 mAs, approximately 640 frames) using a standard Perspex cylindrical body phantom (diameter 32 cm, length 15 cm) and a 10-cm-long pencil ionization chamber. We have found that known displacements were correctly calculated by the registration software to within 1.3 mm and 0.4°. For the anthropomorphic phantom, only translational displacements have been considered. Both studies have shown errors within the intrinsic uncertainty of our system for translational displacements (estimated as 0.87 mm) and rotational displacements (estimated as 0.22°). The resulting table translations proposed by the system to correct the displacements were also checked with portal images and found to place the isocenter of the plan on the linac isocenter within an error of 1 mm, which is the dimension of the spherical lead marker inserted at the center of the homemade phantom. The registration matrix translated into the TPS image fusion module correctly reproduced the alignment between planning CT scans and CBCT scans. Finally, measurements on the CBCT dose index indicate that CBCT acquisition delivers less dose than conventional CT scans and electronic portal imaging device portals. The registration software was found to be accurate, and its registration matrix can be easily translated into the TPS and a low dose is delivered to the patient during image acquisition. These results can help in designing imaging protocols for offline evaluations. [Copyright &y& Elsevier]

The article discusses a research on the identification of defective fas function and variation of the perforin gene in an epidermodysplasia verruciformis patient lacking EVER1 and EVER2 Mutations. It states that epidermodysplasia verruciformis (EV), an infrequently reported lifelong clinical entity, is characterized by abnormal susceptibility to human papillomaviruses (HPVs).