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It has been recently observed that fundamental aspects of the classical theory of factorization can be greatly generalized by combining the languages of monoids and preorders. This has led to various theorems on the existence of certain factorizations, herein called $\preceq$-factorizations, for the $\preceq$-non-units of a (multiplicatively written) monoid $H$ endowed with a preorder $\preceq$, where an element $u \in H$ is a $\preceq$-unit if $u \preceq 1_H \preceq u$ and a $\preceq$-non-unit otherwise. The ``building blocks'' of these factorizations are the $\preceq$-irreducibles of $H$ (i.e., the $\preceq$-non-units $a \in H$ that cannot be written as a product of two $\preceq$-non-units each of which is strictly $\preceq$-smaller than $a$); and it is interesting to look for sufficient conditions for the $\preceq$-factorizations of a $\preceq$-non-unit to be bounded in length or finite in number (if measured or counted in a suitable way). This is precisely the kind of questions addressed in the present work, whose main novelty is the study of the interaction between minimal $\preceq$-factorizations (i.e., a refinement of $\preceq$-factorizations used to counter the ``blow-up phenomena'' that are inherent to factorization in non-commutative or non-cancellative monoids) and some finiteness conditions describing the ``local behaviour'' of the pair $(H, \preceq)$. Besides a number of examples and remarks, the paper includes many arithmetic results, a part of which are new already in the basic case where $\preceq$ is the divisibility preorder on $H$ (and hence in the setup of the classical theory)., Comment: 27 pages, 2 figures. Final version to appear in Journal of Algebra

Cutaneous angiosarcoma (CAS) is the most common type of angiosarcoma that predominantly affects older Caucasians. The outcomes of immunotherapy in CAS are currently under investigation in relation to the expression of programmed death ligand 1 (PD-L1) and other biomarkers. We performed a systematic review and metanalysis of data from the current literature reporting on PD-L1 immunohistochemistry expression. A systematic search of publications in the electronic databases PubMed, Web of Science, and Scopus was conducted using the following terms: “PD-L1” and “angiosarcomas”. A total of ten studies reporting on 279 cases were identified and included in the meta-analysis. The pooled prevalence of PD-L1 expression in CAS was 54% (95% CI 36–71%), with high heterogeneity (I2 = 84.81%, p < 0.001). In sub-group analysis, the proportion of PD-L1 expression in CAS was significantly (p = 0.049) lower in Asian studies (ES = 35%, 95% CI 28–42%, I2 = 0.0%, p = 0.46) than in European studies (ES = 71%, 95% CI 51–89%, I2 = 48.91%, p = 0.12).

Refractory subhemispheric epilepsy has been traditionally treated by resection. The last few decades have seen the emergence of disconnective techniques, for both hemispheric and subhemispheric disease. The aim of this study was to describe the technique for a disconnective surgery for large epileptogenic lesions involving the central (perirolandic cortices), parietal, and occipital lobes. This junctional cortex within the hemisphere (in contrast to anterior and posterior quadrantotomies) presents unique challenges when contemplating a complete disconnection of the region. The surgical technique is achieved through six distinct steps: fronto-central, inferior frontoparietal, lateral temporo-occipital, medial frontal, basal temporo-occipital, and posterior parasagittal callosal disconnections. The functional neuroanatomy of each step is described, along with cadaveric dissections. The authors describe this technique and include a case description of a young girl who presented with childhood-onset intractable epilepsy associated with cognitive stagnation. The postoperative seizure outcome in this patient remains excellent at 2 years’ follow-up, with gains in cognition and behavior. Excellent seizure outcomes can be achieved if the network encompassing the entire epileptogenic cortex is disconnected while ensuring preservation of fiber systems that link functionally eloquent uninvolved cortices adjacent to the central quadrant.

Objective: We aimed to identify factors independently associated with the need for inotropic support for low cardiac output or haemodynamic instability after pulmonary artery banding surgery for CHD. Methods: We performed a retrospective chart review of all neonates and infants who underwent pulmonary banding between January 2016 and June 2019 at our institution. Bivariate and multivariable analyses were performed to identify factors independently associated with the use of post-operative inotropic support, defined as the initiation of inotropic infusion(s) for depressed myocardial function, hypotension, or compromised perfusion within 24 hours of pulmonary artery banding. Results: We reviewed 61 patients. Median age at surgery was 10 days (25%,75%:7,30). Cardiac anatomy was biventricular in 38 patients (62%), hypoplastic right ventricle in 14 patients (23%), and hypoplastic left ventricle in 9 patients (15%). Inotropic support was implemented in 30 patients (49%). Baseline characteristics of patients who received inotropic support, including ventricular anatomy and pre-operative ventricular function, were not statistically different from the rest of the cohort. Patients who received inotropic support, however, were exposed to larger cumulative doses of ketamine intraoperatively – median 4.0 mg/kg (25%,75%:2.8,5.9) versus 1.8 mg/kg (25%,75%:0.9,4.5), p < 0.001. In a multivariable model, cumulative ketamine dose greater than 2.5mg/kg was associated with post-operative inotropic support (odds ratio 5.5; 95% confidence interval: 1.7,17.8), independent of total surgery time. Conclusions: Inotropic support was administered in approximately half of patients who underwent pulmonary artery banding and more commonly occurred in patients who received higher cumulative doses of ketamine intraoperatively, independent of the duration of surgery.

Marginal land exploitation devoted to versatile crops, such as giant reed, is related to the degree of land marginality. Two experiments were conducted in two sites of Sardinia (Italy) to investigate the effects of management on dry matter yield and water productivity (WP). Experiment 1 compared four crop evapotranspiration restoring treatments (100%, 75%, 50%, 25%, and a rainfed control) over 5 years. Experiment 2 lasted 7 years and investigated zero-input supply on crop response. Experiment 1, notwithstanding well-watered conditions (Irr100), showed a higher value of biomass production during the last year monitored, but yielding only 13.5 Mg DM ha−1 and with no significant difference from Irr75. Moreover, being equal the average dry matter yield, in the Irr100, we would save 3630 m3 of irrigation water by achieving the same WP recorded in the Irr25 (25% ETc restoring). Experiment 2, being equal rainfall amount, raised WP values that picked 8.2 kg m−3 during 2018. Results indicate that in less favourable soils as the Experiment 1, well-watered conditions do not ensure better crop growth and productivity, whereas in deep soils (Experiment 2) promising productive results, as well as ecosystem services, could be obtained without any input supply.

Multiple sclerosis is the most common immune-mediated disorder affecting the central nervous system in young adults but still has no cure. Bacillus Calmette–Guérin (BCG) vaccine is reported to have non-specific anti-inflammatory effects and therapeutic benefits in autoimmune disorders including multiple sclerosis. However, the precise mechanism of action of BCG and the host immune response to it remain unclear. In this study, we aimed to investigate the efficacy of the BCG Tokyo-172 vaccine in suppressing experimental autoimmune encephalomyelitis (EAE). Groups of young and mature adult female C57BL/6J mice were BCG-vaccinated 1 month prior or 6 days after active EAE induction using myelin oligodendrocyte glycoprotein (MOG)35–55 peptide. Another group of 2D2 TCRMOG transgenic female mice was BCG-vaccinated before and after the onset of spontaneous EAE. BCG had an age-associated protective effect against active EAE only in wild-type mice vaccinated 1 month before EAE induction. Furthermore, the incidence of spontaneous EAE was significantly lower in BCG vaccinated 2D2 mice than in non-vaccinated controls. Protection against EAE was associated with reduced splenic T-cell proliferation in response to MOG35–55 peptide together with high frequency of CD8+ interleukin-10-secreting T cells in the spleen. In addition, microglia and astrocytes isolated from BCG-vaccinated mice showed polarization to anti-inflammatory M2 and A2 phenotypes, respectively. Our data provide new insights into the cell-mediated and humoral immune mechanisms underlying BCG vaccine-induced neuroprotection, potentially useful for developing better strategies for the treatment of MS.

Background Hydrocephalus is one of the major complications of aneurysmal subarachnoid haemorrhage (aSAH). In the acute setting, an external ventricular drain (EVD) is used for early management. A cisternal drain (CD) coupled with the micro-surgical opening of basal cisterns can be an alternative when the aneurysm is clipped. Chronic hydrocephalus after aSAH is managed with ventriculo-peritoneal (VP) shunt, a procedure associated with a wide range of complications. The aim of this study is to analyse the impact of micro-surgical opening of basal cisterns coupled with CD on the incidence of VP shunt, compared to patients treated with EVD. Methods The authors conducted a retrospective review of 89 consecutive cases of patients with aSAH treated surgically and endovascularly with either EVD or CD between January 2009 and September 2021. Patients were stratified into two groups: Group 1 included patients with EVD, Group 2 included patients with CD. Subgroup analysis with only patients treated surgically was also performed. We compared their baseline characteristics, clinical outcomes and shunting rates. Results There were no statistically significant differences between the two groups in terms of epidemiological characteristics, WFNS score, Fisher scale, presence of intraventricular hemorrhage (IVH), acute hydrocephalus, postoperative meningitis or of clinical outcomes at last follow-up. Cisternostomy with CD (Group 2) was associated with a statistically significant reduction in VP-shunt compared with the use of an EVD (Group 1) (9.09% vs 53.78%; p p = 0.02). Conclusions Cisternostomy with CD may reduce the rate of shunt-dependent hydrocephalus. Cisternostomy allows the removal of subarachnoid blood, thereby reducing arachnoid inflammation and fibrosis. CD may enhance this effect, thus resulting in lower rates of chronic hydrocephalus.

ObjectivesTo identify key disease pathways driving conventional dendritic cell (cDC) alterations in Systemic Sclerosis (SSc).MethodsTranscriptomic profiling was performed on peripheral blood CD1c+ cDCs (cDC2s) isolated from 12 healthy donors and 48 SSc patients with all major disease subtypes. Differential expression analysis comparing the different SSc subtypes and healthy donors was performed to uncover genes dysregulated in SSc. To identify biologically relevant pathways, a gene co-expression network was built using Weighted Gene Correlation Network Analysis. We validated the role of key transcriptional regulators using ChIP-sequencing and in vitro functional assays.ResultsWe identified 17 modules of co-expressed genes in cDC2s that correlated with SSc subtypes and key clinical traits including auto-antibodies, skin score, and occurrence of interstitial lung disease. A module of immune regulatory genes was markedly down regulated in patients with the diffuse SSc subtype characterized by severe fibrosis. Transcriptional regulatory network analysis performed on this module predicted NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes as the key transcriptional mediators of inflammation. Indeed, ChIP-sequencing analysis supported that these NR4A members target numerous differentially expressed genes in SSc cDC2s. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDC2s and modulates downstream T-cell activation.ConclusionsNR4A1, NR4A2 and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDC2s. Thus, the NR4A family represent novel potential targets to restore cDC homeostasis in SSc.KEY MESSAGESWhat is already known about this subject?CD1c+ conventional dendritic cells (cDC2s) are implicated as key players in Systemic Sclerosis (SSc), but key molecular mechanisms underlying their dysregulation were unknown.What does this study add?Transcriptomic analysis and network analysis identified modules of coexpressed genes in cDC2s that correlated with SSc subtypes and key clinical traits.The NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes act as master regulators of key immune regulatory genes dysregulated in SSc cDC2s, as shown by multi-omics integration analysis using transcriptomics and targeted ChIP-sequencing.Pharmacological activation of NR4As inhibits pro-inflammatory cytokine production and CD4+ T-cell activation by cDC2s.How might this impact on clinical practice or future developments?NR4As are attractive candidates for novel treatment options to attenuate pro-inflammatory and pro-fibrotic responses in SSc patients.

To explore the feasibility of using an adaptive behaviour profile (ABP) assessment generated from a well-known measure-the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)-as an instrument for outcome measures in adolescents and adults with Dravet syndrome.We administered the VABS-II to 35 adolescents and adults with Dravet syndrome (15 males; mean age 24 years, SD 8 years, range: 12-46 years) and collected epilepsy history and neurological features at the time of assessment. We conducted a cross-sectional analysis of VABS-II raw scores and performed cluster analysis to identify different subgroups. We then explored possible relationships between clinical and epilepsy features, ABPs, and age.Most participants obtained the minimum standard scores in the various VABS-II subdomains, while the raw score analysis outlined interindividual and intraindividual differences among skills. We found two subpopulations: one with a 'lower' ABP and one with a 'higher' ABP, corresponding respectively to individuals in whom myoclonic seizures or generalized spike-and-wave activity were present ('complete phenotype') or absent ('incomplete phenotype') on electroencephalography.This study further delineates the natural history of Dravet syndrome. The assessment of an ABP through the VABS-II raw score analysis provides a means by which to illustrate profiles of adaptive behaviour in adolescents and adults with Dravet syndrome but shows limitations related to poor sensitivity in measuring fine clinical details. There is a need for new and more specific tools to monitor patients with developmental and epileptic encephalopathies.

A long-standing debate concerns whether developmental dyscalculia is characterized by core deficits in processing nonsymbolic or symbolic numerical information as well as the role of domain-general difficulties. Heterogeneity in recruitment and diagnostic criteria make it difficult to disentangle this issue. Here, we selected children ( n = 58) with severely compromised mathematical skills (2 SD below average) but average domain-general skills from a large sample referred for clinical assessment of learning disabilities. From the same sample, we selected a control group of children ( n = 42) matched for IQ, age, and visuospatial memory but with average mathematical skills. Children with dyscalculia showed deficits in both symbolic and nonsymbolic number sense assessed with simple computerized tasks. Performance in the digit-comparison task and the numerosity match-to-sample task reliably separated children with developmental dyscalculia from controls in cross-validated logistic regression (area under the curve = .84). These results support a number-sense-deficit theory and highlight basic numerical abilities that could be targeted for early identification of at-risk children as well as for intervention.

Although distribution databases are a dynamic tool, continuously updated, it is important to take “snapshots” of the species distribution over time to promptly identify potential conservation issues. With this work, we provide an update of the distribution of amphibians and reptiles in Sardinia and satellite islands. Data derive from both direct field observations (carried out since 2005 until July 2022) and literature, accounting for over 7000 records: 1416 records of 11 species of amphibians and 5600 records of 18 species of reptiles. Distribution maps (on 10 × 10 km UTM grid) of 29 species are provided in supplementary materials as well as the updated list of the amphibians and reptiles occurring in the circum-Sardinian islands. Most of the meshes were characterized by the presence of 1-3 amphibian species (73%) and 6-8 or 9-11 reptile species (32% with 6-8 species, 30% with 9-11 species). Species abundance was favoured by environmental heterogeneity, and mostly varied in relation to elevation range and edge density.

Objective Aesthetic assessment after surgery for non-syndromic single suture craniosynostosis (SSC) is crucial. Surgeons’ evaluation is generally based on Whitaker classification, while parental impression is generally neglected. The aim of this paper is to compare aesthetic perceptions of parents and surgeons after surgery for SSC, expressed by a 10-item questionnaire that complement Whitaker’s classification. Methods The authors submitted a 10-item questionnaire integrating Whitaker’s classification in order to evaluate the degree of satisfaction, the detailed aesthetics results and the need for surgical revision, to surgeons and parents of a consecutive series of patients operated for SSC between January 2007 and December 2018. The results were collected blindly. Results A total of 70 patients were included in the study. Scaphocephaly and trigonocephaly were the two most frequent craniosynostosis. Parents and surgeons general aesthetics evaluation and average rating for Whitaker’s classification were 1.86 vs 1.67 (p = 0.69) and 1.19 vs 1.1 (p = 0.45) respectively. Parents’ evaluation for scar perception and alopecia (p p p = 0.02) are significantly worse when compared to surgeons’ perception. Conclusions Parents seem to be more sensitive to the detection of some aesthetic anomalies and their opinion should not be neglected. The authors propose a modified Whitaker classification based on their results to better stratify the aesthetic outcome after surgery for SSC.

Archaea synthesize isoprenoid-based ether-linked membrane lipids, which enable them to withstand extreme environmental conditions, such as high temperatures, high salinity, and low or high pH values1–5. In some archaea, such as Methanocaldococcus jannaschii, these lipids are further modified by forming carbon–carbon bonds between the termini of two lipid tails within one glycerophospholipid to generate the macrocyclic archaeol or forming two carbon–carbon bonds between the termini of two lipid tails from two glycerophospholipids to generate the macrocycle glycerol dibiphytanyl glycerol tetraether (GDGT)1,2. GDGT contains two 40-carbon lipid chains (biphytanyl chains) that span both leaflets of the membrane, providing enhanced stability to extreme conditions. How these specialized lipids are formed has puzzled scientists for decades. The reaction necessitates the coupling of two completely inert sp3-hybridized carbon centres, which, to our knowledge, has not been observed in nature. Here we show that the gene product of mj0619 from M. jannaschii, which encodes a radical S-adenosylmethionine enzyme, is responsible for biphytanyl chain formation during synthesis of both the macrocyclic archaeol and GDGT membrane lipids6. Structures of the enzyme show the presence of four metallocofactors: three [Fe4S4] clusters and one mononuclear rubredoxin-like iron ion. In vitro mechanistic studies show that Csp3–Csp3 bond formation takes place on fully saturated archaeal lipid substrates and involves an intermediate bond between the substrate carbon and a sulfur of one of the [Fe4S4] clusters. Our results not only establish the biosynthetic route for tetraether formation but also improve the use of GDGT in GDGT-based paleoclimatology indices7–10.

Contrast-enhanced ultrasound (CEUS) is considered a secondary examination compared to computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of hepatocellular carcinoma (HCC), due to the risk of misdiagnosing intrahepatic cholangiocarcinoma (ICC). The introduction of CEUS Liver Imaging Reporting and Data System (CEUS LI-RADS) might overcome this limitation. Even though data from the literature seems promising, its reliability in real-life context has not been well-established yet.To test the accuracy of CEUS LI-RADS for correctly diagnosing HCC and ICC in cirrhosis.CEUS LI-RADS class was retrospectively assigned to 511 nodules identified in 269 patients suffering from liver cirrhosis. The diagnostic standard for all nodules was either biopsy (102 nodules) or CT/MRI (409 nodules). Common diagnostic accuracy indexes such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed for the following associations: CEUS LR-5 and HCC; CEUS LR-4 and 5 merged class and HCC; CEUS LR-M and ICC; and CEUS LR-3 and malignancy. The frequency of malignant lesions in CEUS LR-3 subgroups with different CEUS patterns was also determined. Inter-rater agreement for CEUS LI-RADS class assignment and for major CEUS pattern identification was evaluated.CEUS LR-5 predicted HCC with a 67.6% sensitivity, 97.7% specificity, and 99.3% PPV (CEUS LI-RADS is effective but can be improved by merging LR-4 and 5 to diagnose HCC and by splitting LR-3 into two subgroups to differentiate iso-iso nodules from other patterns.

Internal oxidation of Fe–2.25Cr has been studied in Fe/FeO Rhines pack (RP) and H2/H2O gas mixtures at 700–900 °C. A novel exposure technique allowing RP experiments in dual atmosphere conditions was developed. No measurable effect of hydrogen on lattice oxygen permeability in ferrite could be detected: neither in single nor in dual atmosphere conditions. The H2/H2O atmosphere was found to induce stronger oxidation attack at alloy grain boundaries resulting in a morphology similar to intergranular stress corrosion cracking often reported in nuclear technology. The intergranular oxidation attack was demonstrated to be independent of the dual atmosphere effect, i.e., hydrogen dissolved in the alloy.

OBJECTIVE Lateral periinsular hemispherotomy (LPH) and vertical parasagittal hemispherotomy (VPH) are the most popular disconnective techniques for intractable epilepsies associated with unilateral hemispheric pathologies. The authors aimed to investigate possible differences in seizure outcome and complication rates between patients who underwent LPH and VPH. METHODS A comprehensive literature search of PubMed and Embase identified English-language articles published from database inception to December 2019 that reported series (minimum 12 patients with follow-up ≥ 12 months) on either LPH or VPH. Pooled rates of seizure freedom and complications (with a particular focus on hydrocephalus) were analyzed using meta-analysis to calculate both fixed and random effects. Heterogeneity (Cochran’s Q test) and inconsistency (fraction of Q due to actual heterogeneity) were also calculated. RESULTS Twenty-five studies were included. Data from 825 patients were available for seizure outcome analysis (583 underwent LPH and 242 underwent VPH), and data from 692 patients were available for complication analysis (453 underwent LPH and 239 underwent VPH). No differences were found in the pooled rates of Engel class I seizure outcome between patients who underwent LPH (80.02% and 79.44% with fixed and random effects, respectively) and VPH (79.89% and 80.69% with fixed and random effects, respectively) (p = 0.953). No differences were observed in the pooled rates of shunted hydrocephalus between patients who underwent LPH (11.34% and 10.63% with fixed and random effects, respectively) and VPH (11.07% and 9.98% with fixed and random effects, respectively) (p = 0.898). Significant heterogeneity and moderate inconsistency were determined for hydrocephalus occurrence in patients who underwent both LPH and VPH. CONCLUSIONS LPH and VPH techniques present similar excellent seizure outcomes, with comparable and acceptable safety profiles.

Summary This study aims to investigate the level of genetic variability of Fasciola hepatica flukes isolated from cattle in Algeria and to determine the phylogenetic and phylogeographic relationships with sequences isolated worldwide. Mitochondrial (Cytochrome c Oxidase subunit I gene - COI) and nuclear markers (Internal Transcribed Spacers of nuclear ribosomal DNA - ITS) for 24 F. hepatica flukes isolated from 12 cattle in North Algeria were characterised. Only two haplotypes were obtained for the COI gene, resulting in a low level of genetic variation. The analysis of variation among the COI sequences isolated from around the world did not show high levels of genetic divergence, and the phylogenetic analysis revealed a genetic similarity among F. hepatica isolates from different areas of the world. The analysis of the ITS region showed a low level of variability, which prevented obtaining informative phylogenetic and phylogeographic results. The present study also revealed that specimens of F. hepatica are genetically similar in different hosts, indicating that the genetic structure among populations of this parasite is not influenced by the host species. The low levels of genetic variation for COI and ITS regions among fluke isolates from all continents are consistent with a common origin for the flukes’ worldwide distribution.

Objective: The objective is to verify whether a genetic condition associated with bipolar disorder (BD) is frequent in old adults adapted to their environment, without BD, but with aptitudes for hyperactivity and novelty seeking (H/NS). Methods: In this cross-sectional study, the study sample included healthy elderly people (40 participants, aged 60 or older) living in an urban area and recruited from a previous study on physical exercise and active aging, who were compared with 21 old adults with BD from the same area. The genetic methodology consisted of blood sampling, DNA extraction, real-time PCR jointly with FRET probes, and the SANGER sequencing method. The genetic variant RS1006737 of CACNA1C, found to be associated with bipolar disorder diagnosis, was investigated. Results: The frequency of the RS1006737 genetic variant in the study group (H/NS) is not higher than in the BD group and is statistically significantly higher than in all the control groups found in the literature. However, the familiarity for BD is higher in old adults with BD than in the H/NS sample without BD. The risk of BD in the family (also considering those without BD but with family members with BD) is not associated with the presence of the genetic variant examined. Conclusion: The study suggests that the gene examined is associated with characteristics of hyperactivity rather than just BD. Nevertheless, choosing to participate in an exercise program is an excessively general way to identify H/NS. The next step would be to identify the old adults with well-defined H/NS features with an adequate tool.

Objective: This paper illustrates the preliminary psychometric properties of the Questionnaire for Adaptive Hyperactivity and Goal Achievement (AHGA), aimed at measuring adaptive characteristics of hyperactivity and goal pursuit in older adults. Methods: The 12-item scale was administered to a sample of 120 subjects (older adults) between February 2022 and June 2022. The reliability of AHGA was measured using Cronbach’s alpha, and factor structure was established using parallel analysis (PA) and principal component analysis (PCA). Convergent validity was tested against the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN). Results: All included subjects have an average age of 74.1±5.1 years. AHGA reliability was good (Cronbach’s alpha: 0.713 [95%CI: 0.630 to 0.783]). Factor analysis suggested two main components: goal achievement and hyperactivity, which explained 41% of the variance in the data. The results support the convergent validity of the scale: AHGA measures adaptive characteristics of hyperactivity and goal pursuit, in contrast to BRIAN, which measures pathological characteristics. Conclusion: The reported findings represent an innovative approach to hyperthymic features by embracing a broader spectrum concept that conceptualizes the potential transition between pathological and adaptive aspects as a continuum.

Histone modifications regulate chromatin remodeling and gene expression in development and diseases. DOT1L, the sole histone H3K79 methyltransferase, is essential for embryonic development. Here, we report that DOT1L regulates male fertility in mouse. DOT1L associates with MLLT10 in testis. DOT1L and MLLT10 localize to the sex chromatin in meiotic and post-meiotic germ cells in an inter-dependent manner. Loss of either DOT1L or MLLT10 leads to reduced testis weight, decreased sperm count and male subfertility. H3K79me2 is abundant in elongating spermatids, which undergo the dramatic histone-to-protamine transition. Both DOT1L and MLLT10 are essential for H3K79me2 modification in germ cells. Strikingly, histones are substantially retained in epididymal sperm from either DOT1L- or MLLT10-deficient mice. These results demonstrate that H3K79 methylation promotes histone replacement during spermiogenesis.

Job’s syndrome, or autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES, STAT3-Dominant Negative), is a rare inborn error of immunity (IEI) with multi-organ involvement and long-life post-infective damage. Longitudinal registries are of primary importance in improving our knowledge of the natural history and management of these rare disorders. This study aimed to describe the natural history of 30 Italian patients with AD-HIES recorded in the Italian network for primary immunodeficiency (IPINet) registry. This study shows the incidence of manifestations present at the time of diagnosis versus those that arose during follow up at a referral center for IEI. The mean time of diagnostic delay was 13.7 years, while the age of disease onset was

Supplementary Figure 1. Activation of the CDK4/6 axis in human intrahepatic cholangiocarcinoma (ICC) specimens. Supplementary Figure 2. Levels of Rb1, CDK4, CDK6, E2F1, and Cyclin E1 mRNA in human intrahepatic cholangiocarcinoma (ICC) from The Cancer Genome Atlas (TCGA) and National Cancer Institute (NCI) datasets. Supplementary Figure 3: Effect of Palbociclib on ICC cell growth. Supplementary Figure 4: Effect of Palbociclib on the levels of putative target proteins in human ICC cell lines. Supplementary Figure 5. Inhibition of CyclinD1 (CCND1) expression enhances tumor cell growth suppressor capacity of Palbobiclib. Supplementary Figure 6. Correlation analysis of Retinoblastoma (Rb) expression and the growth inhibitory effects of Palbociclib. Supplementary Figure 7. Palbociclib inhibits proliferation of ICC cell lines in colony formation assays. Supplementary Figure 8. Retinoblastoma-dependent cell growth inhibition effect of long-term Palbociclib treatment in ICC cells. Supplementary Figure 9. Effect of combined Palbociclib/MLN0128 treatment on cell proliferation. Supplementary Figure 10. Synergistic effect of Palbociclib/MLN0128 combination in ICC cell lines. Supplementary Figure 11. Effect of combined Palbociclib/MLN0128 administration on cell cycle of ICC cell lines. Supplementary Figure 12. Effect of Palbociclib/MLN0128 on putative target proteins in intrahepatic cholangiocarcinoma (ICC) cell lines. Supplementary Figure 13. Overview of the apoptosis rate in ICC lesions from AKT/YapS127A mice subjected to the various treatment regimens. Supplementary Figure 14. Effect of Palbociclib/MLN0128 treatment on putative target proteins in AKT/YapS127A mice. Supplementary Table 1: Clinicopathological features of intrahepatic cholangiocarcinoma (ICC) patients Supplementary Table 2: Western blotting antibody information

Fig S2. Technical validation using NuGEN's Ovation System. The scatter plot shows the fold change consistency of genes differentially expressed using WG-DASL and NuGEN methods. Only 6 out of the 509 DE genes were found discordant, confirming the WG-DASL patterns. Data are plotted as log2 fold change (FC) expression long/short PFS; positive log2(FC) values stand for genes up-regulated in long-PFS cases, while negative values stand for up-regulation in short-PFS cases. Statistical significance was tested through Monte Carlo test (1000 interactions) yielding p-value

Fig S1. Volcano plot for the 17,378 genes detected by microarray analysis. The x-axis is the fold-change, and the y-axis is log10 p value. A total of 509 probes (blue dots) were differentially expressed in long-PFS patients (14) compared with short-PFS patients (26), imposing a FDR < 15%. Probability of finding by chance 509 significant DE genes between the classes: p = 0.016.

FigS3: Biasogram representing the influence of tissue origin on outcome. Y axes indicate the outcome vector (long- versus short- PFS), while B indicates the nuisance variable (tissue origin; primary versus recurrence/metastatic). The colorgram represents a bivariate histogram of all the 17,378 detected genes; the green circles indicate the genes present in our signature.

Purpose:Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer type, lacking effective therapies and associated with a dismal prognosis. Palbociclib is a selective CDK4/6 inhibitor, which has been shown to suppress cell proliferation in many experimental cancer models. Recently, we demonstrated that pan-mTOR inhibitors, such as MLN0128, effectively induce apoptosis, although have limited efficacy in restraining proliferation of ICC cells. Here, we tested the hypothesis that palbociclib, due to its antproliferative properties in many cancer types, might synergize with MLN0128 to impair ICC growth.Experimental Design:Human ICC cell lines and the AKT/YapS127A ICC mouse model were used to test the therapeutic efficacy of palbociclib and MLN0128, either alone or in combination.Results:Administration of palbociclib suppressed in vitro ICC cell growth by inhibiting cell-cycle progression. Concomitant administration of palbociclib and MLN0128 led to a pronounced, synergistic growth constraint of ICC cell lines. Furthermore, while treatment with palbociclib or MLN0128 alone resulted in tumor growth reduction in AKT/YapS127A mice, a remarkable tumor regression was achieved when the two drugs were administered simultaneously. Mechanistically, palbociclib was found to potentiate MLN0128 mTOR inhibition activity, whereas MLN0128 prevented the upregulation of cyclin D1 induced by palbociclib treatment.Conclusions:Our study indicates the synergistic activity of palbociclib and MLN0128 in inhibiting ICC cell proliferation. Thus, combination of CDK4/6 and mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against human ICC.See related commentary by Malumbres, p. 6

Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent–metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961–70. ©2016 AACR.See related commentary by Chau and Hammerman, p. 3710