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Convergent transcription, that is, the collision of sense and antisense transcription, is ubiquitous in mammalian genomes and believed to diminish RNA expression. Recently, antisense transcription downstream of promoters was found to be surprisingly prevalent. However, functional characteristics of affected promoters are poorly investigated. Here we show that convergent transcription marks an unexpected positively co-regulated promoter constellation. By assessing transcriptional dynamic systems, we identified co-regulated constituent promoters connected through a distinct chromatin structure. Within these cis-regulatory domains, transcription factors can regulate both constituting promoters by binding to only one of them. Convergent promoters comprise about a quarter of all active transcript start sites and initiate 5′-overlapping antisense RNAs—an RNA class believed previously to be rare. Visualization of nascent RNA molecules reveals convergent cotranscription at these loci. Together, our results demonstrate that co-regulated convergent promoters substantially expand the cis-regulatory repertoire, reveal limitations of the transcription interference model and call for adjusting the promoter concept.

AbstractPeople live their lives and experience the conflicts in which they are involved in the context of competing normative orders. But how do people navigate this normative pluralism? To understand this, Keebet von Benda-Beckmann’s model of ‘forum shopping’ and ‘shopping forums’, derived from an ethnographic analysis of conflict resolution, remains an indispensable starting point. Building on this approach, I argue that in order to understand the navigation of normative orders more broadly, it is important to bring the analysis of sentiments to the study of normative pluralism. Drawing on ethnographic fieldwork on the International Criminal Court’s transitional justice interventions in northern Uganda, I argue that when confronted with different international, national, religious, and indigenous normative options for dealing with mass violence, people navigate normative pluralism by creating, mobilising, maintaining, and transforming sentiments.

Growing evidence suggests that somatic mutations may be a major cause of the aging process. However, it remains to be tested whether the predictions of the theory also apply to species with longer life spans than humans. Hydrais a genus of freshwater polyps with remarkable regeneration abilities and a potentially unlimited life span under laboratory conditions. By genome sequencing of single cells and whole animals, we found that the mutation rates in Hydra’s stem cells are even slightly higher than in humans or mice. A potential explanation for this deviation from the prediction of the theory may lie in the adaptability offered by a higher mutation rate, as we were able to show that the genome of the widely studied Hydra magnipapillata strain 105 has undergone a process of strong positive selection since the strain's cultivation 50 years ago. This most likely represents a rapid adaptation to the drastically altered environmental conditions associated with the transition from the wild to laboratory conditions. Processes under positive selection in captive animals include pathways associated with Hydra’s simple nervous system, its nucleic acid metabolic process, cell migration, and hydrolase activity.

Notre base recueille les cas de carcinomes épidermoïdes cutanés (CEC) traités par voie systémique depuis 2020. Nous avions montré chez les 142 premiers patients que ceux-ci étaient caractérisés par une fréquence élevée de patients immunodéprimés et de patients avec un PS altéré et que les anti-PD-1 étaient administrés en 1religne dans la majorité des cas. Nous actualisons les données et présentons pour la première fois les données de réponse et de survie des patients sous anti-PD(L)-1.

Immunotherapy has become the standard of care for several types of cancer, such as melanoma. However, it can induce toxicity, including immune checkpoint inhibitor–induced colitis (CIC). CIC shares several clinical, histological, biological, and therapeutic features with inflammatory bowel disease (IBD). Clostridium difficileinfection (CDI) can complicate the evolution of IBD. We aimed to characterize the association between CDI and CIC in patients treated with anti-CTLA-4 and anti-PD-1 for melanoma. Patients from nine centers treated with anti-CTLA-4 and anti-PD-1 for melanoma and presenting with CDI from 2010 to 2021 were included in this retrospective cohort. The primary endpoint was the occurrence of CIC. The secondary endpoints were findings allowing us to characterize CDI. Eighteen patients were included. Eleven were treated with anti-PD-1, four with anti-CTLA-4, and three with anti-PD-1 in combination with anti-CTLA-4. Among the 18 patients, six had isolated CDI and 12 had CIC and CDI. Among these 12 patients, eight had CIC complicated by CDI, three had concurrent CIC and CDI, and one had CDI followed by CIC. CDI was fulminant in three patients. Endoscopic and histological features did not specifically differentiate CDI from CIC. Nine of 11 patients required immunosuppressive therapy when CDI was associated with CIC. In nine cases, immunotherapy was discontinued due to digestive toxicity. CDI can be isolated or can complicate or reveal CIC. CDI in patients treated with immunotherapy shares many characteristics with CDI complicating IBD. Stool tests for Clostridium difficileshould be carried out for all patients with diarrhea who are being treated with immunotherapy.

BackgroundDuring closed reduction of displaced distal radius fractures, physical examination is used to determine the need for further manipulation before radiographic confirmation and cast application. Manipulation performed under ultrasound guidance has the potential to decrease the number of reduction attempts.MethodsThis multicentre randomised controlled trial was undertaken between December 2018 and July 2020 in the ED of four hospitals in the Netherlands. Patients aged ≥16 years presenting to the ED with a distal radius fracture requiring closed reduction were randomised to either point-of-care ultrasound (PoCUS)-guided or standard reduction. The primary outcome was the proportion of patients requiring more than one reduction attempt. The secondary outcomes were time to complete reduction and treatment plan at ED discharge (conservative or operative repair).ResultsA total of 214 patients were screened, of which 211 patients were included for primary endpoint analysis (87% female, median age 68 years, 94% dorsal angulation, 59% intra-articular and 73% multifragmentary). In total, 105 patients were randomised to standard treatment and 106 patients to PoCUS-guided fracture reduction. In the standard treatment group, 13 patients (12%) required more than one reduction attempt, compared with 6 patients (6%) in the PoCUS group (OR 2.35, 95% CI 0.86 to 6.45). The median reduction time was 5 min in the PoCUS group (IQR 3–6) vs 3 min (IQR 2–4) in the standard reduction group (p<0.001). At ED discharge, operative repair was indicated for 17 (16%) patients in the standard group and 21 (20%) patients in the PoCUS group (OR 0.78, 95% CI 0.39 to 1.58).ConclusionThis study could not demonstrate that PoCUS-guided reduction of distal radius fractures was associated with a statistically significant decrease in the number of reduction attempts.Trial registration numberThe Netherlands Trial Register (NTR7934).

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection.

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1or (rarely) SMARCA4causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising from other central nervous system tumors have been reported. Malignant gliomas, IDH wild-type, arising in patients with Li-Fraumeni syndrome typically show somatic mutations of TP53as well as complex copy number alterations, but little is known about the loss of SMARCB1 or SMARCA4 protein expression in this context. Here, we report 2 children in whom malignant supratentorial brain tumors with SMARCB1 deficiency, complex copy number alterations, and somatic TP53mutations lead to the discovery of pathogenic/likely pathogenic TP53variants in the germline. Screening of the molecularneuropathology.org dataset for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4 deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1-deficient or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somatic TP53mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53germline status.

Le carcinome de Merkel (CCM) est un cancer de mauvais pronostic, dont le risque de récidive est estimé à 40 %. Les facteurs de risque de récidive sont essentiellement le stade tumoral au diagnostic et l’immunodépression. Cependant, peu de données sont disponibles sur le devenir des patients après une première récidive. Notre objectif était d’étudier le devenir des patients après une première récidive de CMM.

Le carcinome épidermoïde cutané (CEC) évolue rarement vers une forme localement évoluée ou métastatique. Des essais évaluant les anti PD-1 ont montré un taux de réponse proche de 50 % avec des réponses souvent prolongées. Depuis juillet 2019, le cémiplimab est autorisé en Europe mais reste non remboursé. Notre objectif était ici d’étudier les caractéristiques des patients recevant une 1religne de traitement systémique et celles de leur traitement.

Le carcinome de Merkel (CCM) est un cancer agressif, dont la survie à 5 ans est estimée à 40 %. Les inhibiteurs de checkpoint (ICP) anti-PD-1/PD-L1 ont modifié le pronostic des patients métastatiques. Les facteurs de réponse aux ICP ne sont pas connus. Notre objectif était d’évaluer la survie et les facteurs de réponse aux ICP chez des patients ayant un CCM avancé.

Dryland slopes, fluvial fans and terraces are recognized as highly sensitive process-response systems and important geoarchives for the reconstruction of palaeoclimatic driven landscape development in Southern Africa. The aim of this study is to study a dryland drainage system with a clearly limited regional catchment area, whose drainage and sedimentation behavior is unaffected by distant meteorological events or changes in climatic outside the region. Our results highlight for the first time the widespread occurrence of fluvial and lacustrine sediments in the Naukluft Mts. foreland as part of the Great Escarpment and their potential as Late Quaternary geoarchives. The region’s special interest and overarching value lies (i) in the bounded catchments of both the lacustrine BüllsPort Playa and the ephemeral rivers Tsauchab and Tsondab within the South African Great Escarpment and (ii) in the rivers’ endorheic character and dead ends within the Namib Sand Sea to the West. All these lacustrine and fluvial systems first and foremost exclude supra-regional influences within the flow regime. Uniquely, the key palaeoclimatic question of periodical shifts of the rainfall zones during Holocene and Late Glacial times can be studied in both these catchments. This study also combines new data from the semi-desert environment of the Naukluft Mts. with data from the terminus sites Sossusvlei and Tsondabvlei within the Namib dunes. From our interpretation of the desert flash flood series, the drainage history from pre-LGM times within MIS 3 up to modern times is represented in our data. The Late Termination I was the period with the highest flow rates post MIS3, raising the Urikos Terrace. This must have been caused by strong monsoonal rainfall events from summer TTT, giving rise to extreme flash floods. Little Ice Age sediments have filled the entire thalweg, with the exception of remnant Holocene to MIS 3 terraces to the sides and provide a unique framework for ecological conditions.

Human resource for health information system (HRHIS) is an application that collects, stores and analyses health worker-related data, which can be utilised for stress level detection. HRHIS is expected to provide information about the health worker condition. This paper is a pilot project for a larger project which aims to define the fundamental predictor variables for stress level detection in HRHIS. The purpose of this pilot project is to review the needs to utilise the HRHIS as a tool for detecting stress level. To find out the current psychological state of health workers, we used a list of questions related to their mental condition and life satisfaction. The result of this research shows that health workers experience conditions that may cause stress at work and influence their ability to concentrate, sleep quality, and decision-making ability.

This work reports on the synthesis and in-depth electrochemical and photochemical characterization of two chromium(0) and molydenum(0) metal complexes with bidentate pyridyl-mesoionic carbene (MIC) ligands of the 1,2,3-triazol-5-ylidene type and carbonyl coligands. Metal complexes with MIC ligands have turned out to have very promising electrocatalytic and photochemical properties, but examples of MIC-containing complexes with early-transition-metal centers remain extremely rare. The electrochemistry of these new MIC complexes was studied by cyclic voltammetry and especially spectroelectrochemistry in the IR region consistent with a mainly metal-centered oxidation, which is fully reversible in the case of the chromium(0) complex. At the same time, the two reduction steps are predominantly ligand-centered according to the observed near-IR absorbance, with the first reduction step being reversible for both systems. The results of the electron paramagnetic resonance studies on the oxidized and reduced species confirm the IR spectroelectrochemistry experiments. The photochemical reactivity of the complexes with a series of organic ligands was investigated by time-resolved (step-scan) Fourier transform infrared (FTIR) spectroscopy. Interestingly, the photoreactions in pyridine and acetonitrile are fully reversible with a slow dark reverse reaction back to the educt species over minutes and even hours, depending on the metal center and reagent. This reversible behavior is in contrast to the expected loss of one or several CO ligands known from related homoleptic as well as heteroleptic M(CO)4L2α-diimine transition-metal complexes.

Cinq cas d’éruption induite à tropisme sébacé (EITS) liée à la consommation d’extrait de kava-kava ont été décrits dans la littérature médicale sous le nom de « sebotropic drug reaction ». Nous rapportons un cas après consommation de pollen d’abeille.

A gold(III) complex with the hitherto most electron poor mesoionic carbene ligand is presented. Aqua regia was the oxidizing agent of choice for the synthesis of this unusual organometallic compound. The AuIIIcomplex is redox-rich and also acts as a catalyst for oxazole formation, delivering selectively a completely different isomer in comparison to its AuIcongener.

To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.

In 2008, Feng et al. identified Merkel cell polyomavirus integration as the primary oncogenic event in ~80% of Merkel cell carcinoma cases. The remaining virus-negative Merkel cell carcinoma cases associated with a high mutational load are most likely caused by UV radiation. The current study aimed to compare the morphological and immunohistochemical features of 80 virus-positive and 21 virus-negative Merkel cell carcinoma cases. Microscopic evaluation revealed that elongated nuclei—similar to the spindle-shape variant of small cell lung cancer—were less frequent in Merkel cell polyomavirus-positive Merkel cell carcinoma compared to the virus-negative subset (p= 0.005). Moreover, virus-negative cases more frequently displayed a “large-cell neuroendocrine carcinoma” phenotype with larger cell size (p= 0.0026), abundant cytoplasm (p= 4×10−7) and prominent nucleoli (p= 0.002). Analysis of immunohistochemical data revealed frequent positivity for thyroid transcription factor 1 and cytokeratin 7, either absence or overexpression of p53, as well as frequent lack of neurofilament expression in virus-negative cases. By contrast, cytokeratin 8, 18 and 20 and a CD99 with a dot pattern as well as high EMA expression were identified as characteristic features of virus-positive Merkel cell carcinoma. In particular, the CD99 dot-like expression pattern was strongly associated with presence of the Merkel cell polyomavirus in Merkel cell carcinoma (sensitivity = 81%, specificity = 90%, positive likelihood ratio = 8.08). To conclude, virus-positive and -negative Merkel cell carcinoma are characterized by distinct morphological and immunohistochemical features, which implies a significant difference in tumor biology and behavior. Importantly, we identified the CD99 staining pattern as a marker indicating the virus status of this skin cancer.

In 2008, Feng et al. identified Merkel cell polyomavirus integration as the primary oncogenic event in ~80% of Merkel cell carcinoma cases. The remaining virus-negative Merkel cell carcinoma cases associated with a high mutational load are most likely caused by UV radiation. The current study aimed to compare the morphological and immunohistochemical features of 80 virus-positive and 21 virus-negative Merkel cell carcinoma cases. Microscopic evaluation revealed that elongated nuclei—similar to the spindle-shape variant of small cell lung cancer—were less frequent in Merkel cell polyomavirus-positive Merkel cell carcinoma compared to the virus-negative subset (p= 0.005). Moreover, virus-negative cases more frequently displayed a “large-cell neuroendocrine carcinoma” phenotype with larger cell size (p= 0.0026), abundant cytoplasm (p= 4×10−7) and prominent nucleoli (p= 0.002). Analysis of immunohistochemical data revealed frequent positivity for thyroid transcription factor 1 and cytokeratin 7, either absence or overexpression of p53, as well as frequent lack of neurofilament expression in virus-negative cases. By contrast, cytokeratin 8, 18 and 20 and a CD99 with a dot pattern as well as high EMA expression were identified as characteristic features of virus-positive Merkel cell carcinoma. In particular, the CD99 dot-like expression pattern was strongly associated with presence of the Merkel cell polyomavirus in Merkel cell carcinoma (sensitivity = 81%, specificity = 90%, positive likelihood ratio = 8.08). To conclude, virus-positive and -negative Merkel cell carcinoma are characterized by distinct morphological and immunohistochemical features, which implies a significant difference in tumor biology and behavior. Importantly, we identified the CD99 staining pattern as a marker indicating the virus status of this skin cancer.

ABSTRACTThis study is based on 616 geochronological ages from aeolian and colluvial sediments as well as paleosols, representing the largest database of geochronological data from northeastern Germany available to date. Cumulative probability density functions for radiocarbon data and kernel density estimates for luminescence data were created covering the last 15 ka. The data analysis aimed at the identification of changes and their drivers in geomorphodynamics and soil formation. The ages representing aeolian activity cluster in the Late Glacial, the Early Holocene, and the Late Holocene, where the first two clusters are assumed to result mostly from climatic impact with only a minor share of human impact triggering the mobilization of aeolian sediments. The third cluster is considered to result mainly from human impact. The Late Glacial to Early Holocene activity phase is interrupted by a phase of surface stability around 11.5–12.7 ka, which is indicated by the occurrence of initial soil formations of Finow and Usselo types. Colluvial sedimentation predominantly occurred during the last 7 ka and clearly accelerated since the last 1000 a. According to the ages of specific paleosol types, related soil-forming processes started already in the Late Glacial and were completed in the Holocene.

Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin mostly induced by Merkel cell polyomavirus integration. Cytokeratin 20 (CK20) positivity is currently used to distinguish Merkel cell carcinomas from other neuroendocrine carcinomas. However, this distinction may be challenging in CK20-negative cases and in cases without a primary skin tumor. The objectives of this study were first to evaluate the diagnostic accuracy of previously described markers for the diagnosis of Merkel cell carcinoma and second to validate these markers in the setting of difficult-to-diagnose Merkel cell carcinoma variants. In a preliminary set (n= 30), we assessed optimal immunohistochemical patterns (CK20, thyroid transcription factor 1 [TTF-1], atonal homolog 1 [ATOH1], neurofilament [NF], special AT-rich sequence-binding protein 2 [SATB2], paired box protein 5, terminal desoxynucleotidyl transferase, CD99, mucin 1, and Merkel cell polyomavirus-large T antigen) and Merkel cell polyomavirus load thresholds (real-time PCR). The diagnostic accuracy of each marker was then assessed in a validation set of 103 Merkel cell carcinomas (9 CK20-negative cases and 15 cases without a primary skin tumor) and 70 extracutaneous neuroendocrine carcinoma cases. The most discriminant markers for a diagnosis of Merkel cell carcinoma were SATB2, NF expression, and Merkel cell polyomavirus DNA detection (positive likelihood ratios: 36.6, 44.4, and 28.2, respectively). Regarding Merkel cell carcinoma variants, cases without a primary skin tumor retained a similar immunohistochemical  profile and CK20-negative tumors displayed a different profile (decrease frequency of NF and SATB2 expression), but Merkel cell polyomavirus DNA remained detected (78% of cases by qPCR). Moreover, 8/9 (89%) CK20-negative Merkel cell carcinoma cases but only 3/61 (5%) CK20-negative extracutaneous neuroendocrine cases were positive for at least one of these markers. In conclusion, detection of SATB2 and NF expression and Merkel cell polyomavirus DNA helps distinguish between Merkel cell carcinoma classical and variant cases and extracutaneous neuroendocrine carcinomas.

Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin mostly induced by Merkel cell polyomavirus integration. Cytokeratin 20 (CK20) positivity is currently used to distinguish Merkel cell carcinomas from other neuroendocrine carcinomas. However, this distinction may be challenging in CK20-negative cases and in cases without a primary skin tumor. The objectives of this study were first to evaluate the diagnostic accuracy of previously described markers for the diagnosis of Merkel cell carcinoma and second to validate these markers in the setting of difficult-to-diagnose Merkel cell carcinoma variants. In a preliminary set (n= 30), we assessed optimal immunohistochemical patterns (CK20, thyroid transcription factor 1 [TTF-1], atonal homolog 1 [ATOH1], neurofilament [NF], special AT-rich sequence-binding protein 2 [SATB2], paired box protein 5, terminal desoxynucleotidyl transferase, CD99, mucin 1, and Merkel cell polyomavirus-large T antigen) and Merkel cell polyomavirus load thresholds (real-time PCR). The diagnostic accuracy of each marker was then assessed in a validation set of 103 Merkel cell carcinomas (9 CK20-negative cases and 15 cases without a primary skin tumor) and 70 extracutaneous neuroendocrine carcinoma cases. The most discriminant markers for a diagnosis of Merkel cell carcinoma were SATB2, NF expression, and Merkel cell polyomavirus DNA detection (positive likelihood ratios: 36.6, 44.4, and 28.2, respectively). Regarding Merkel cell carcinoma variants, cases without a primary skin tumor retained a similar immunohistochemical  profile and CK20-negative tumors displayed a different profile (decrease frequency of NF and SATB2 expression), but Merkel cell polyomavirus DNA remained detected (78% of cases by qPCR). Moreover, 8/9 (89%) CK20-negative Merkel cell carcinoma cases but only 3/61 (5%) CK20-negative extracutaneous neuroendocrine cases were positive for at least one of these markers. In conclusion, detection of SATB2 and NF expression and Merkel cell polyomavirus DNA helps distinguish between Merkel cell carcinoma classical and variant cases and extracutaneous neuroendocrine carcinomas.

The new recently described provisional lymphoma category Burkitt-like lymphoma with 11q aberration comprises cases similar to Burkitt lymphoma (BL) on morphological, immunophenotypic and gene-expression levels but lacking the IG-MYC translocation. They are characterized by a peculiar imbalance pattern on chromosome 11, but the landscape of mutations is not yet described. Thus, we investigated 15 MYC-negative Burkitt-like lymphoma with 11q aberration (mnBLL,11q,) cases by copy-number analysis and whole-exome sequencing. We refined the regions of 11q imbalance and identified the INO80 complex-associated gene NFRKB as a positional candidate in 11q24.3. Next to recurrent gains in 12q13.11-q24.32 and 7q34-qter as well as losses in 13q32.3-q34, we identified 47 genes recurrently affected by protein-changing mutations (each =3 of 15 cases). Strikingly, we did not detect recurrent mutations in genes of the ID3-TCF3 axis or the SWI/SNF complex that are frequently altered in BL, or in genes frequently mutated in germinal center–derived B-cell lymphomas like KMT2D or CREBBP. An exception is GNA13, which was mutated in 7 of 15 cases. We conclude that the genomic landscape of mnBLL,11q, differs from that of BL both at the chromosomal and mutational levels. Our findings implicate that mnBLL,11q, is a lymphoma category distinct from BL at the molecular level.

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1- MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1-/D2- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1-/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1- MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1- MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1- MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1-/D2-/D3- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1- MCL.

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1−MCL has been recognized, and approximately one-half of them harbor CCND2translocations while the primary event in cyclin D1−/D2−MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1−/SOX11+MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2rearrangements in 39 cases (70%) but not CCND3rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3(6 cases) and CCND2(4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1−MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1and CCNE2.These cases had blastoid morphology, high genomic complexity, and CDKN2Aand RB1deletions. Both genomic and gene-expression profiles of cyclin D1−MCL cases were indistinguishable from cyclin D1+MCL. In conclusion, virtually all cyclin D1−MCLs carry CCND2/CCND3rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1−/D2−/D3−MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1−MCL.

The new recently described provisional lymphoma category Burkitt-like lymphoma with 11q aberration comprises cases similar to Burkitt lymphoma (BL) on morphological, immunophenotypic and gene-expression levels but lacking the IG-MYCtranslocation. They are characterized by a peculiar imbalance pattern on chromosome 11, but the landscape of mutations is not yet described. Thus, we investigated 15 MYC-negative Burkitt-like lymphoma with 11q aberration (mnBLL,11q,) cases by copy-number analysis and whole-exome sequencing. We refined the regions of 11q imbalance and identified the INO80 complex-associated gene NFRKBas a positional candidate in 11q24.3. Next to recurrent gains in 12q13.11-q24.32 and 7q34-qter as well as losses in 13q32.3-q34, we identified 47 genes recurrently affected by protein-changing mutations (each ≥3 of 15 cases). Strikingly, we did not detect recurrent mutations in genes of the ID3-TCF3 axis or the SWI/SNF complex that are frequently altered in BL, or in genes frequently mutated in germinal center–derived B-cell lymphomas like KMT2Dor CREBBP. An exception is GNA13, which was mutated in 7 of 15 cases. We conclude that the genomic landscape of mnBLL,11q, differs from that of BL both at the chromosomal and mutational levels. Our findings implicate that mnBLL,11q, is a lymphoma category distinct from BL at the molecular level.

Rare cases of aggressive B-cell lymphomas with a morphology similar to Burkitt lymphoma (BL) present with the BL-typical immunophenotype, but lacked MYCtranslocation (MYC-negative Burkitt-like lymphoma: mnBLL). A proportion of those with an imbalance pattern in chromosome 11q has been designated Burkitt-like lymphoma with 11q aberrationin the recent update of the World Health Organization (WHO) classification. Because of the problems in the identification of Burkitt-like lymphoma with 11q aberration, our goal was to retrospectively analyze their frequency in a cohort of “candidate” aggressive lymphomas (cohort 1, n=35) such as mnBLL (n=16), diffuse large B-cell lymphoma with similarities to Burkitt lymphoma (DLBCL-BL; n=3), high-grade B-cell lymphomas, not otherwise specified (NOS) (n=16), as well as in a cohort of MYC-negative diffuse large B-cell lymphoma NOS (cohort 2, n=62). In total, 17/33 cohort 1 cases (52%) harbored the typical 11q aberration pattern, predominantly those that had been classified as mnBLL (12/16, 75%), but also as DLBCL-BL (2/3, 67%) and high-grade B-cell lymphomas, NOS (3/14; 21%). The specimens with this typical 11q aberration pattern were usually negative for the BCL2 protein. Of interest and as a new finding, samples harboring the 11q aberration pattern were often characterized by strikingly coarse apoptotic debris within starry sky macrophages facilitating their recognition. In contrast, only 1 of 62 garden variety DLBCL, NOS was positive for the 11q aberration pattern. In 2 DLBCL-BL, a dual MYCtranslocation/11q aberration pattern was detected. As a diagnostic algorithm, we, therefore, propose analysis of 11q status in MYC-negative high-grade lymphomas with features of BL, especially showing BCL2 negativity and a conspicuous coarse apoptotic debris in starry sky macrophages.

Le mélanome de Dubreuilh ou lentigo malin (LM) est une prolifération mélanocytaire survenant sur une peau photo-exposée qui peut évoluer vers un mélanome invasif. La chirurgie est recommandée comme traitement de première intention, avec des marges d’exérèse de 5 à 10mm, sans consensus international. Plusieurs études ont montré que l’imiquimod, un immunomodulateur, pouvait induire une régression du LM. Nous avons donc mené une étude visant à évaluer l’effet de l’imiquimod par rapport à un placebo en néoadjuvant dans le traitement du LM.

ABSTRACTControl of systemic and hepatic inflammation, in particular originating from monocytes/macrophages, is crucial to prevent liver fibrosis and its progression to end-stage cirrhosis. LC3-associated phagocytosis (LAP) is a non-canonical form of autophagy that shifts the monocyte/macrophage phenotype to an anti-inflammatory phenotype. In a recent study, we uncovered LAP as a protective mechanism against inflammation-driven liver fibrosis and systemic inflammation in the context of cirrhosis. We observed that LAP is enhanced in blood and liver monocytes from patients with liver fibrosis or those who progress to cirrhosis. Combining studies in which LAP was pharmacologically or genetically inactivated, we found that LAP limits inflammation in monocytes from cirrhotic patients, and the hepatic inflammatory profile in mice with chronic liver injury, resulting in anti-fibrogenic effects. Mechanistically, LAP-induced anti-inflammatory and antifibrogenic signaling results from enhanced expression of the Fc immunoreceptor FCGR2A/FcγRIIA and activation of an FCGR2A-mediated PTPN6/SHP-1 anti-inflammatory pathway, leading to increased engulfment of IgG into LC3 +phagosomes. In patients with cirrhosis progressing to multi-organ failure (acute-on chronic liver failure), LAP is lost in monocytes, and can be restored by targeting FCGR2A-mediated PTPN6/SHP-1 signaling. These data suggest that sustaining LAP may open novel therapeutic perspectives for patients with end-stage liver disease.

Inactivating mutations within the AR gene are present in only ~40% of individuals with clinically and hormonally diagnosed androgen insensitivity syndrome (AIS). Previous studies revealed the existence of an AR gene mutation-negative group of patients with AIS who have compromised androgen receptor (AR) function (AIS type II).

AbstractLegal anthropology and legal sociology have much in common. Traditionally, however, these approaches have tried to maintain disciplinary boundaries toward each other. Latest since the 1990s, these boundaries have become more and more porous and the academic practices of boundary-making do seem to convince practitioners of these fields less and less. The recent emergence of a subfield of the anthropology of the state situated at the interface of legal anthropology, legal sociology, ethnographic studies of bureaucracies and organizational sociology attests to this development. In this introduction, we propose to consciously transgress the traditional boundaries between legal anthropology, legal sociology and the anthropology of the state when it comes to the ethnographic investigation of official law. Based on the contributions to this special issue—consisting of empirical articles and commentaries—we map several avenues for boundary transgressions and the theoretical reconceptualizations these may engender. Among them are: looking at legal institutions of the state as practicing both informal formality and formal informality; moving from socio-spatial metaphors to investigating official law-places and -spaces as ethnographic objects; and studying norm-making within official law as a wider field of practice.

AbstractThis article proposes a methodological approach to courtroom ethnography by developing the idea of the courtroom as an affective arrangement. In the courtroom, humans and their linguistic utterances, but also material objects and infrastructures, visuals, voices, and sounds are relationally entangled. This is the analytical entry point for ethnographically describing the atmosphere of a court proceeding without reducing atmosphere either to the result of courtroom talk or to the emotional experiences of the participants. For a thick ethnographic description of courtroom atmospheres, the ethnographer should point out how all kinds of different bodies perform in the theatre of power that is a court proceeding.

Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAFgermline alterations. We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution. For this gene, we further demonstrate whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin–Siris syndrome or late-onset tumors like schwannoma or meningioma (p< 0.0001). SMARCB1germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies (p< 0.001). We attribute variants in specific BAFgenes to certain disease entities. Finally, single-nucleotide variants and indels are sometimes detected in the healthy relatives of tumor patients, while Coffin–Siris syndrome and Nicolaides–Baraitser syndrome generally seem to appear de novo. Our findings add further information on the genotype–phenotype association of germline variants detected in genes of the BAF complex. Functional studies are urgently needed for a deeper understanding of BAF-related disorders and may take advantage from the comprehensive information gathered in this article.

High quality models of factors influencing rice crop yield are needed in countries where rice is a staple food. These models can help select optimal rice varieties for expected field conditions. Development of a system to help scientist track and make decisions using this data is challenging. It involves incorporation of complex data structures - genomic, phenotypic, and remote sensing - with computationally intensive statistical modeling. In this article, the authors present a web portal designed to help researchers to manage and analyze their datasets, apply machine learning to detect how factors taken together influence crop production, and summarize the results to help scientists make decisions based on the learned models. The authors developed the system to be easily accessed by the entire team including rice scientist, genetics, and farmers. As such, they developed a system on a server architecture comprised of a SQLite database, a web interface developed in Python, the Celery job scheduler, and statistical computing in R.

Supplemental Digital Content is available in the text.Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly encountered in infants. Mutations of the SMARCB1gene are the characteristic genetic lesion. A small group of ATRT stands out clinically, because these tumors are located in the sellar region of adults. To investigate if sellar region ATRT in adults represents a molecular distinct entity, we characterized molecular alterations in 7 sellar region ATRTs in adults as compared with 150 pediatric ATRTs and 47 pituitary adenomas using SMARCB1sequencing, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization as well as DNA methylation profiling. The median age of the 6 female and 1 male patients was 56 years. On histopathologic examination, all tumors were malignant rhabdoid tumors showing loss of SMARCB1/INI1 protein expression. Two cases displayed compound heterozygous SMARCB1point mutations, 3 cases showed heterozygous SMARCB1deletions with point mutations of the other allele and 1 case a homozygous SMARCB1deletion; in 1 case, underlying SMARCB1alterations could not be identified. On unsupervised hierarchical cluster analysis of DNA methylation profiles, sellar region ATRTs did not form a distinct group, but clustered with ATRT-MYC, 1 of 3 recently described molecular subgroups of ATRT. On analysis of DNA methylation array intensity data, only 1 sellar region ATRT showed characteristic features of pediatric ATRT-MYC, that is, major copy number losses affecting the SMARCB1region. In conclusion, these results suggest that sellar region ATRTs in adults form a clinically distinct entity with a different mutational spectrum, but epigenetic similarities with pediatric ATRTs of the ATRT-MYC subgroup.