A temperate Earth-sized planet with tidal heating transiting an M6 star.

Temperate Earth-sized exoplanets around late-M dwarfs offer a rare opportunity to explore under which conditions planets can develop hospitable climate conditions. The small stellar radius amplifies the atmospheric transit signature, making even compact secondary atmospheres dominated by N2 or CO2 amenable to characterization with existing instrumentation1. Yet, despite large planet search efforts2, detection of low-temperature Earth-sized planets around late-M dwarfs has remained rare and the TRAPPIST-1 system, a resonance chain of rocky planets with seemingly identical compositions, has not yet shown any evidence of volatiles in the system3. Here we report the discovery of a temperate Earth-sized planet orbiting the cool M6 dwarf LP 791-18. The newly discovered planet, LP 791-18d, has a radius of 1.03 ± 0.04 R⊕ and an equilibrium temperature of 300-400 K, with the permanent night side plausibly allowing for water condensation. LP 791-18d is part of a coplanar system4 and provides a so-far unique opportunity to investigate a temperate exo-Earth in a system with a sub-Neptune that retained its gas or volatile envelope. On the basis of observations of transit timing variations, we find a mass of 7.1 ± 0.7 M⊕ for the sub-Neptune LP 791-18c and a mass of [Formula: see text] for the exo-Earth LP 791-18d. The gravitational interaction with the sub-Neptune prevents the complete circularization of LP 791-18d's orbit, resulting in continued tidal heating of LP 791-18d's interior and probably strong volcanic activity at the surface5,6.

TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion.

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.

The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries.

Bromodomain and extraterminal motif (BET) proteins are pharmacologic targets for the treatment of diverse diseases, yet the roles of individual BET family members remain unclear. We find that BRD2, but not BRD4, co-localizes with the architectural/insulator protein CCCTC-binding factor (CTCF) genome-wide. CTCF recruits BRD2 to co-bound sites whereas BRD2 is dispensable for CTCF occupancy. Disruption of a CTCF/BRD2-occupied element positioned between two unrelated genes enables regulatory influence to spread from one gene to another, suggesting that CTCF and BRD2 form a transcriptional boundary. Accordingly, single-molecule mRNA fluorescence in situ hybridization (FISH) reveals that, upon site-specific CTCF disruption or BRD2 depletion, expression of the two genes becomes increasingly correlated. HiC shows that BRD2 depletion weakens boundaries co-occupied by CTCF and BRD2, but not those that lack BRD2. These findings indicate that BRD2 supports boundary activity, and they raise the possibility that pharmacologic BET inhibitors can influence gene expression in part by perturbing domain boundary function.

Newly identified nematodes from the Great Salt Lake are associated with microbialites and specially adapted to hypersaline conditions.

Extreme environments enable the study of simplified food-webs and serve as models for evolutionary bottlenecks and early Earth ecology. We investigated the biodiversity of invertebrate meiofauna in the benthic zone of the Great Salt Lake (GSL), Utah, USA, one of the most hypersaline lake systems in the world. The hypersaline bays within the GSL are currently thought to support only two multicellular animals: brine fly larvae and brine shrimp. Here, we report the presence, habitat, and microbial interactions of novel free-living nematodes. Nematode diversity drops dramatically along a salinity gradient from a freshwater river into the south arm of the lake. In Gilbert Bay, nematodes primarily inhabit reef-like organosedimentary structures built by bacteria called microbialites. These structures likely provide a protective barrier to UV and aridity, and bacterial associations within them may support life in hypersaline environments. Notably, sampling from Owens Lake, another terminal lake in the Great Basin that lacks microbialites, did not recover nematodes from similar salinities. Phylogenetic divergence suggests that GSL nematodes represent previously undescribed members of the family Monhysteridae-one of the dominant fauna of the abyssal zone and deep-sea hydrothermal vents. These findings update our understanding of halophile ecosystems and the habitable limit of animals.

A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Chronic Rhinosinusitis Risk after Maxillectomy with Microvascular Reconstruction.

INTRODUCTION: Chronic rhinosinusitis (CRS) can be associated with tumors involving the maxillary sinus, but outcomes after undergoing maxillectomy with free flap reconstruction remain unclear. METHODS: A retrospective analysis of medical records was performed to evaluate evidence of CRS in patients who underwent maxillectomy with free flap reconstruction at a single tertiary care academic institution from 2013 through 2020. RESULTS: Eighty-four patients were assessed. Nineteen (22.6%) patients were diagnosed with CRS after surgery, 23 (27.4%) patients were treated for sinus symptoms, and 49 (58.3%) had radiographic evidence of sinus inflammation for more than 6 months. Risk factors for requiring sinus treatment included adjuvant or neoadjuvant chemotherapy (p = 0.002) and pre-operative use of sinus medication (p < 0.001). Radiographic evidence of sinusitis 6 months after surgery is also closely associated with sinusitis treatment (p = 0.051). CONCLUSIONS: CRS may be underdiagnosed in patients undergoing maxillectomy with microvascular reconstruction. Further evaluation into patient sinus disease and symptoms following neoplastic surgery may lead to a higher quality of life in some long-term survivors.

An exploration into the relationship between insomnia and repetitive negative thinking among cancer survivors.

OBJECTIVE: Insomnia and repetitive negative thinking (RNT) are both prevalent among cancer survivors, yet little work has investigated their interrelationship. To explore the hypothesis that RNT and insomnia are related, we conducted secondary analyses on data from a pilot clinical trial of cognitive behavioral therapy for insomnia (CBT-I) for cancer survivors. METHODS: This study analyzed survey data from 40 cancer survivors with insomnia who participated in a pilot randomized trial of CBT-I. Correlations and linear regression models were used to determine associations between aspects of RNT and related constructs (fear of cancer recurrence [FCR], cancer-specific rumination, worry, and intolerance of uncertainty) and sleep (insomnia and sleep quality), while accounting for psychiatric symptoms such as anxiety and depression. Treatment-related change in RNT was examined using a series of linear mixed models. RESULTS: Evidence for an association between RNT and insomnia among cancer survivors emerged. Higher levels of FCR and cancer-related rumination were correlated with more severe insomnia symptoms and worse sleep quality. Notably, FCR levels predicted insomnia, even after controlling for anxiety and depression. Results identified potential benefits and limitations of CBT-I in addressing RNT that should be examined more thoroughly in future research. CONCLUSIONS: RNT is a potential target to consider in insomnia treatment for cancer survivors.

New era for myelofibrosis treatment with novel agents beyond Janus kinase-inhibitor monotherapy: Focus on clinical development of BCL-XL /BCL-2 inhibition with navitoclax.

Myelofibrosis is a heterogeneous myeloproliferative neoplasm characterized by chronic inflammation, progressive bone marrow failure, and hepatosplenic extramedullary hematopoiesis. Treatments like Janus kinase inhibitor monotherapy (e.g., ruxolitinib) provide significant spleen and symptom relief but demonstrate limited ability to lead to a durable disease modification. There is an urgent unmet medical need for treatments with a novel mechanism of action that can modify the underlying pathophysiology and affect the disease course of myelofibrosis. This review highlights the role of B-cell lymphoma (BCL) protein BCL-extra large (BCL-XL ) in disease pathogenesis and the potential role that navitoclax, a BCL-extra large/BCL-2 inhibitor, may have in myelofibrosis treatment.

Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.

Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887_890delTAAG (p.Val296Glyfs∗13), in exon 5; this frameshift introduces a stop codon in amino acid 308 of the growth arrest-specific protein 2-like 2 (GAS2L2). Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867_∗343+1207del; p.?) starting in exon 5. Both individuals had clinical features of PCD but normal ciliary axoneme structure. In this research, using human nasal cells, mouse models, and X.laevis embryos, we show that GAS2L2 is abundant at the apical surface of ciliated cells, where it localizes with basal bodies, basal feet, rootlets, and actin filaments. Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern. These results were recapitulated in Gas2l2-/- mouse tracheal epithelial cell (mTEC) cultures and in X. laevis embryos treated with Gas2l2 morpholinos. In mice, the absence of Gas2l2 caused neonatal death, and the conditional deletion of Gas2l2 impaired mucociliary clearance (MCC) and led to mucus accumulation. These results show that a pathogenic variant in GAS2L2 causes a genetic defect in ciliary orientation and impairs MCC and results in PCD.

Land-use intensification causes multitrophic homogenization of grassland communities.

Land-use intensification is a major driver of biodiversity loss. Alongside reductions in local species diversity, biotic homogenization at larger spatial scales is of great concern for conservation. Biotic homogenization means a decrease in ß-diversity (the compositional dissimilarity between sites). Most studies have investigated losses in local (α)-diversity and neglected biodiversity loss at larger spatial scales. Studies addressing ß-diversity have focused on single or a few organism groups (for example, ref. 4), and it is thus unknown whether land-use intensification homogenizes communities at different trophic levels, above- and belowground. Here we show that even moderate increases in local land-use intensity (LUI) cause biotic homogenization across microbial, plant and animal groups, both above- and belowground, and that this is largely independent of changes in α-diversity. We analysed a unique grassland biodiversity dataset, with abundances of more than 4,000 species belonging to 12 trophic groups. LUI, and, in particular, high mowing intensity, had consistent effects on ß-diversity across groups, causing a homogenization of soil microbial, fungal pathogen, plant and arthropod communities. These effects were nonlinear and the strongest declines in ß-diversity occurred in the transition from extensively managed to intermediate intensity grassland. LUI tended to reduce local α-diversity in aboveground groups, whereas the α-diversity increased in belowground groups. Correlations between the ß-diversity of different groups, particularly between plants and their consumers, became weaker at high LUI. This suggests a loss of specialist species and is further evidence for biotic homogenization. The consistently negative effects of LUI on landscape-scale biodiversity underscore the high value of extensively managed grasslands for conserving multitrophic biodiversity and ecosystem service provision. Indeed, biotic homogenization rather than local diversity loss could prove to be the most substantial consequence of land-use intensification.

Comparative structure-function analysis of bromodomain and extraterminal motif (BET) proteins in a gene-complementation system.

The widely expressed bromodomain and extraterminal motif (BET) proteins bromodomain-containing protein 2 (BRD2), BRD3, and BRD4 are multifunctional transcriptional regulators that bind acetylated chromatin via their conserved tandem bromodomains. Small molecules that target BET bromodomains are being tested for various diseases but typically do not discern between BET family members. Genomic distributions and protein partners of BET proteins have been described, but the basis for differences in BET protein function within a given lineage remains unclear. By establishing a gene knockout-rescue system in a Brd2-null erythroblast cell line, here we compared a series of mutant and chimeric BET proteins for their ability to modulate cell growth, differentiation, and gene expression. We found that the BET N-terminal halves bearing the bromodomains convey marked differences in protein stability but do not account for specificity in BET protein function. Instead, when BET proteins were expressed at comparable levels, their specificity was largely determined by the C-terminal half. Remarkably, a chimeric BET protein comprising the N-terminal half of the structurally similar short BRD4 isoform (BRD4S) and the C-terminal half of BRD2 functioned similarly to intact BRD2. We traced part of the BRD2-specific activity to a previously uncharacterized short segment predicted to harbor a coiled-coil (CC) domain. Deleting the CC segment impaired BRD2's ability to restore growth and differentiation, and the CC region functioned in conjunction with the adjacent ET domain to impart BRD2-like activity onto BRD4S. In summary, our results identify distinct BET protein domains that regulate protein turnover and biological activities.

Nematode biphasic 'boom and bust' dynamics are dependent on host bacterial load while linking dauer and mouth-form polyphenisms.

Cross-kingdom interactions involve dynamic processes that shape terrestrial ecosystems and represent striking examples of co-evolution. The multifaceted relationships of entomopathogenic nematodes with their insect hosts and symbiotic bacteria are well-studied cases of co-evolution and pathogenicity. In contrast, microbial interactions in soil after the natural death of insects and other invertebrates are minimally understood. In particular, the turnover and succession of nematodes and bacteria during insect decay have not been well documented - although it represents a rich ecological niche with multiple species interactions. Here, we utilize developmentally plastic nematode Pristionchus pacificus and its associated scarab beetles as models. On La Réunion Island, we collected rhinoceros beetle Oryctes borbonicus, induced death, and placed carcasses in cages both on the island and in a mock-natural environment in the laboratory controlling for high spatial and temporal resolution. Investigating nematode population density and dispersal dynamics, we were able to connect two imperative plasticities, dauer and mouth form. We observed a biphasic 'boom and bust' dispersal dynamic of dauer larvae that corresponds to bacterial load on carcasses but not bacterial type. Strikingly, all post-dauer adults have the predatory mouth form, demonstrating novel intricate interactions on decaying insect hosts. Thus, ecologically relevant survival strategies incorporate critical plastic traits.

Young genes have distinct gene structure, epigenetic profiles, and transcriptional regulation.

Species-specific, new, or "orphan" genes account for 10%-30% of eukaryotic genomes. Although initially considered to have limited function, an increasing number of orphan genes have been shown to provide important phenotypic innovation. How new genes acquire regulatory sequences for proper temporal and spatial expression is unknown. Orphan gene regulation may rely in part on origination in open chromatin adjacent to preexisting promoters, although this has not yet been assessed by genome-wide analysis of chromatin states. Here, we combine taxon-rich nematode phylogenies with Iso-Seq, RNA-seq, ChIP-seq, and ATAC-seq to identify the gene structure and epigenetic signature of orphan genes in the satellite model nematode Pristionchus pacificus Consistent with previous findings, we find young genes are shorter, contain fewer exons, and are on average less strongly expressed than older genes. However, the subset of orphan genes that are expressed exhibit distinct chromatin states from similarly expressed conserved genes. Orphan gene transcription is determined by a lack of repressive histone modifications, confirming long-held hypotheses that open chromatin is important for new gene formation. Yet orphan gene start sites more closely resemble enhancers defined by H3K4me1, H3K27ac, and ATAC-seq peaks, in contrast to conserved genes that exhibit traditional promoters defined by H3K4me3 and H3K27ac. Although the majority of orphan genes are located on chromosome arms that contain high recombination rates and repressive histone marks, strongly expressed orphan genes are more randomly distributed. Our results support a model of new gene origination by rare integration into open chromatin near enhancers.

Intralymphatic immunotherapy for allergic rhinitis: A systematic review and meta-analysis.

Background: Only a fraction of patients with allergic rhinitis receive allergen-specific immunotherapy (AIT). AIT is most commonly delivered subcutaneously in a series of injections over 3-5 years. Common obstacles to completing this therapy include cost and inconvenience. Intralymphatic immunotherapy (ILIT) has been proposed as a faster alternative, which requires as few as three injections spaced 4 weeks apart. Objective: This systematic review and meta-analysis evaluated the current evidence that supports the use of ILIT for allergic rhinitis. Methods: Clinical trials were identified in the published literature by using an electronic search strategy and were evaluated by using a risk of bias tool. Treatment outcome (symptom scores, medication scores, and combined symptom and medication scores) and provocation testing results (nasal provocation and skin-prick testing) were included in a meta-analysis of standardized mean difference with subgrouping by using a random-effects model. Overall adverse event rates were tabulated, and overall risk ratios were calculated by using a random-effects model. Results: We identified 17 clinical trials that met eligibility criteria. The standardized mean difference of ILIT on the symptom and medication score was -0.72 (95% confidence interval [CI], -0.98 to -0.46; p < 0.0001) (n = 10). The standardized mean difference of ILIT on nasal provocation and skin-prick testing was -1.00 (95% CI, -1.38 to -0.61; p < 0.0001) (n = 7) and -0.73 (95% CI, -0.99 to -0.47; p < 0.0001) (n = 7), respectively. No statistically significant heterogeneity was detected. The overall adverse event rate was 39.5% for ILIT and 23.5% for placebo. Also, 98.4% of adverse events were mild. Conclusion: Our meta-analysis demonstrated that ILIT was safe, conferred desensitization to seasonal and nonseasonal allergens, alleviated allergic rhinitis symptoms, and reduced medication use. A larger randomized, double-blind, placebo controlled trial will be necessary for wider adaptation of this form of AIT.

Facile target validation in an animal model with intracellularly expressed monobodies.

Rapidly determining the biological effect of perturbing a site within a potential drug target could guide drug discovery efforts, but it remains challenging. Here, we describe a facile target validation approach that exploits monobodies, small synthetic binding proteins that can be fully functionally expressed in cells. We developed a potent and selective monobody to WDR5, a core component of the mixed lineage leukemia (MLL) methyltransferase complex. The monobody bound to the MLL interaction site of WDR5, the same binding site for small-molecule inhibitors whose efficacy has been demonstrated in cells but not in animals. As a genetically encoded reagent, the monobody inhibited proliferation of an MLL-AF9 cell line in vitro, suppressed its leukemogenesis and conferred a survival benefit in an in vivo mouse leukemia model. The capacity of this approach to readily bridge biochemical, structural, cellular characterization and tests in animal models may accelerate discovery and validation of druggable sites.

On the importance of the innervation of the human cervical longitudinal ligaments at vertebral level.

PURPOSE: In our aging society, the prevalence of degenerative spinal diseases rose drastically within the last years. However, up till now, the origin of cervical pain is incompletely understood. While animal and small cadaver studies indicate that a complex system of sensory and nociceptive nerve fibers in the anterior (ALL) and posterior longitudinal ligament (PLL) at the level of the intervertebral disc might be involved, there is a lack of data exploring whether such a network exists and is equally distributed within the cervical vertebrae (VB). We, therefore, aimed to investigate the spatial distribution of the mentioned nerve networks in human tissue. METHODS: We performed macroscopic (Sihler staining, Spalteholz technique, and Plastination) and microscopic (immunohistochemistry for PGP 9.5 and CGRP) studies to characterize spatial differences in sensory and nociceptive innervation patterns. Therefore, 23 human body donors were dissected from level C3-C6. RESULTS: We could show that there is a focal increase in sensory and nociceptive nerve fibers at the level of C4 and C5 for both ALL and PLL, while we observed less nerve fiber density at the level of C3 and C6. An anatomical vicinity between nerve and vessels was observed. CONCLUSION: To our knowledge, these findings for the first time report spatial differences in sensory and nociceptive nerve fibers in the human cervical spine at VB level. The interconnection between nerves and vessels supports the importance of the perivascular plexus. These findings might be of special interest for clinical practice as many patients suffer from pain after cervical spine surgery.

Physiological in vitro sacroiliac joint motion: a study on three-dimensional posterior pelvic ring kinematics.

The sacroiliac joint (SIJ) is a well-known source of low back and pelvic pain, of increasing interest for both conservative and surgical treatment. Alterations in the kinematics of the pelvis have been hypothesized as a major cause of SIJ-related pain. However, definitions of both the range and the extent of physiological movement are controversial, and there are no clear baseline data for pathological alterations. The present study combined a novel biomechanical setup allowing for physiological motion of the lumbosacral transition and pelvis without restricting the SIJ movement in vitro, combined with optical image correlation. Six fresh human pelvises (81 ± 10 years, three females, three males) were tested, with bodyweight-adapted loading applied to the fifth lumbar vertebra and both acetabula. Deformation at the lumbopelvises was determined computationally from three-dimensional image correlation data. Sacroiliac joint motion under the loading of 100% bodyweight primarily consisted of a z-axis rotation (0.16°) and an inferior translation of the sacrum relative to the ilium (0.32 mm). Sacroiliac joint flexion-extension rotations were minute (< 0.02°). Corresponding movements of the SIJ were found at the lumbosacral transition, with an anterior translation of L5 relative to the sacrum of -0.97 mm and an inferior translation of 0.11 mm, respectively. Moreover, a flexion of 1.82° was observed at the lumbosacral transition. Within the innominate bone and at the pubic symphysis, small complementary rotations were seen around a vertical axis, accounting for -0.10° and 0.11°, respectively. Other motions were minute and accompanied by large interindividual variation. The present study provides evidence of different SIJ motions than reported previously when exerted by physiological loading. Sacroiliac joint kinematics were in the sub-degree and sub-millimeter range, in line with previous in vivo and in vitro findings, largely limited to the sagittal rotation and an inferior translation of the sacrum relative to the ilium. This given physiological loading scenario underlines the relevance of the lumbosacral transition when considering the overall motion of the lumbopelvis, and how relatively little the other segments contribute to overall motion.

Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase physiologically expressed by fetal neural cells. However, aberrantly expressed ALK is involved in the pathogenesis of diverse malignancies, including distinct types of lymphoma, lung carcinoma, and neuroblastoma. The aberrant ALK expression in nonneural cells results from chromosomal translocations that create novel fusion proteins. These protein hybrids compose the proximal part of a partner gene, including its promoter region, and the distal part of ALK, including the coding sequence for the entire kinase domain. ALK was first identified in a subset of T-cell lymphomas with anaplastic large cell lymphoma (ALCL) morphology (ALK+ ALCL), the vast majority of which harbor the well-characterized nucleophosmin (NPM)-ALK fusion protein. NPM-ALK co-opts several intracellular signal transduction pathways, foremost being the STAT3 pathway, normally activated by cytokines from the interleukin-2 (IL-2) family to promote cell proliferation and to inhibit apoptosis. Many genes and proteins modulated by NPM-ALK are also involved in evasion of antitumor immune response, protection from hypoxia, angiogenesis, DNA repair, cell migration and invasiveness, and cell metabolism. In addition, NPM-ALK uses epigenetic silencing mechanisms to downregulate tumor suppressor genes to maintain its own expression. Importantly, NPM-ALK is capable of transforming primary human CD4+ T cells into immortalized cell lines indistinguishable from patient-derived ALK+ ALCL. Preliminary clinical studies indicate that inhibition of NPM-ALK induces long-lasting complete remissions in a large subset of heavily pretreated adult patients and the vast majority of children with high-stage ALK+ ALCL. Combining ALK inhibition with other novel therapeutic modalities should prove even more effective.

The United States of histone ubiquitylation and methylation.

In this issue of Molecular Cell, Wu et al. (2011) reveal that ubiquitylation of histone 2B lysine 34 stimulates histone methyltransferase activity on nucleosomes, a finding with implications for the general mechanism by which monoubiquitylation may influence subsequent modification activities.

Development of the glenohumeral joint after subscapular release and open relocation in children with brachial plexus birth palsy: long-term results in 61 patients.

BACKGROUND: We present the long-term results of remodeling of the glenohumeral joint after open subscapularis elongation and relocation of the humeral head in patients with an internal rotation contracture and joint incongruity due to brachial plexus birth palsy. METHODS: In this before-and-after study, 61 patients who underwent open subscapularis elongation and reduction of the glenohumeral joint were evaluated with respect to joint remodeling, with a mean follow-up period of 10.2 years (range, 7-16 years). The mean age at operation was 3.2 years (range, 8 months to 15 years). Measurements of the percentage of the humeral head anterior to the midscapular line (PHHA), glenoid version, and diameter of the humeral head were recorded using magnetic resonance imaging, comparing the affected joints preoperatively vs. postoperatively (n = 31) and comparing the operated vs. unaffected sides postoperatively (n = 61). RESULTS: The mean increase in PHHA was 27.6 percentage points (95% confidence interval, 22.4-32.7 percentage points; P < .01), from 13.2% to 40.8%. The glenoid retroversion changed by 14.8° (95% confidence interval, 11.1°-18.4°; P < .01), from 25.4° to 10.6°, approaching a normal value. All patients, even those older than 5 years, showed a clear benefit from surgery. CONCLUSIONS: Our study confirms that open subscapularis lengthening with joint repositioning, up to the age of 5 years, gives consistent remodeling of incongruent shoulders with surprisingly small differences between the operated and unaffected shoulders at long-term follow-up. The findings indicate that open reduction is useful also in adolescents and challenges the notion that older children should be treated with derotational humeral osteotomy.