RuPHOX-Ru Catalyzed Asymmetric Cascade Hydrogenation of 3-Substituted Chromones for the Synthesis of Corresponding Chiral Chromanols.

An efficient RuPHOX-Ru catalyzed asymmetric cascade hydrogenation of 3-substituted chromones has been achieved under mild reaction conditions, affording the corresponding chiral 3-substituted chromanols in high yields with excellent enantio- and diastereoselectivities (up to 99 % yield, >99 % ee and >20 : 1 dr). Control reactions and deuterium labelling experiments revealed that a dynamic kinetic resolution process occurs during the subsequent hydrogenation of the C=O double bond, which is responsible for the high performance of the asymmetric cascade hydrogenation. The resulting products allow for several transformations and it was shown that the protocol provides a practical and alternative strategy for the synthesis of chiral 3-substituted chromanols and their derivatives.

Rh-Catalyzed Enantioselective Desymmetric Hydrogenation of α-Acetamido-1,3-indanediones Using Ether-Bridged Biphenyl Diphosphine Ligands.

Novel axially chiral biphenyl diphosphine ligands Enm-BridgePhos, bearing an ether chain bridge at the 5,5'-position of the biphenyl backbone, have been developed and successfully applied in the Rh-catalyzed enantioselective desymmetric hydrogenation of α-acetamido-1,3-indanediones, providing chiral α-acetamido-ß-hydroxybenzocyclic pentones in high yields (up to 97%) and with excellent enantioselectivities (up to 99% ee). The reaction could be carried out on a gram scale, and the corresponding products were used as vital intermediates for the synthesis of analogues of chiral spirobenzylisoquinoline alkaloids. Both the crystal structure analysis and the DFT calculations revealed that the large dihedral angle of the Enm-BridgePhos-Rh complexes is highly related to the excellent enantioselectivities.

Unraveling the Asymmetric O─O Radical Coupling Mechanism on Ru─O─Co for Enhanced Acidic Water Oxidation.

Heterogeneous oxides with multiple interfaces provide significant advantages in electrocatalytic activity and stability. However, controlling the local structure of these oxides is challenging. In this work, unique heterojunctions are demonstrated based on two oxide types, which are formed via pyrolysis of a ruthenocene metal-organic framework (Ru-MOF) at specific temperatures. The resulted Ru-MOF-400 exhibits excellent electrocatalytic activity, with an overpotential of 190 mV at a current density of 10 mA cm-2 in 0.1 m HClO4 , and a mass activity of 2557 A gRu -1 , three orders of magnitude higher than commercial RuO2 . The Ru─O─Co bond formed by the incorporation of Co into the rutile lattice of RuO2 inhibits the disolution of Ru. Operando electrochemical investigations and density functional theory results reveal that the Ru-MOF-400 undergo asymmetric dual-active site oxide path mechanism during the acidic oxygen evolution reaction process, which is predominantly mediated by the asymmetric Ru─Co dual active site present at the interfaces between Co3 O4 and CoRuOx .

Detection approach for GEO space objects with a wide-field optical telescope array.

In 2020, Changchun Observatory developed a 280 mm wide-field optical telescope array to improve surveillance of space debris in the geosynchronous belt. There are many advantages including a wide field of view, the ability to observe a large area of sky and high reliability. However, the wide field of view causes a significant number of background stars to appear in the image when photographing space objects, making it difficult to detect them. This research focuses on the precise detection of GEO space objects from images taken by this telescope array in order to position them in large quantities. Our work further investigates the motion feature of an object, namely that the object can be seen as being in a uniform linear motion for a brief length of time. Based on this feature, the belt can be divided into a number of smaller areas and the telescope array scans each smaller area one at a time from east to west. To detect objects in the subarea, a combination of image differencing with trajectory association is used. The image differencing algorithm is used to remove most stars and screen out suspected objects in the image. Next, the trajectory association algorithm is employed to further filter out the real objects among the suspected ones, and the trajectories attributed to the same object are linked. The feasibility and accuracy of the approach were verified by the experiment results. The accuracy rate of trajectory association exceeds 90% and on average, more than 580 space objects can be detected per observation night. Since the J2000.0 equatorial system can accurately describe the apparent position of an object, the object can be detected by using this coordinate system as opposed to the pixel coordinate system.

Middle age serum sodium levels in the upper part of normal range and risk of heart failure.

AIMS: With increasing prevalence of heart failure (HF) owing to the ageing population, identification of modifiable risk factors is important. In a mouse model, chronic hypohydration induced by lifelong water restriction promotes cardiac fibrosis. Hypohydration elevates serum sodium. Here, we evaluate the association of serum sodium at middle age as a measure of hydration habits with risk to develop HF. METHODS AND RESULTS: We analysed data from Atherosclerosis Risk in Communities study with middle age enrolment (45-66 years) and 25 years of follow-up. Participants without water balance dysregulation were selected: serum sodium within normal range (135-146 mmol/L), not diabetic, not obese and free of HF at baseline (N = 11 814). In time-to-event analysis, HF risk was increased by 39% if middle age serum sodium exceeded 143 mmol/L corresponding to 1% body weight water deficit [hazard ratio 1.39, 95% confidence interval (CI) 1.14-1.70]. In a retrospective case-control analysis performed on 70- to 90-year-old attendees of Visit 5 (N = 4961), serum sodium of 142.5-143 mmol/L was associated with 62% increase in odds of left ventricular hypertrophy (LVH) diagnosis [odds ratio (OR) 1.62, 95% CI 1.03-2.55]. Serum sodium above 143 mmol/L was associated with 107% increase in odds of LVH (OR 2.07, 95% CI 1.30-3.28) and 54% increase in odds of HF (OR 1.54, 95% CI 1.06-2.23). As a result, prevalence of HF and LVH was increased among 70- to 90-year-old participants with higher middle age serum sodium. CONCLUSION: Middle age serum sodium above 142 mmol is a risk factor for LVH and HF. Maintaining good hydration throughout life may slow down decline in cardiac function and decrease prevalence of HF.

Diagnosis and Treatment of Double Thyroglossal Duct Cyst.

This retrospective study aimed to investigate clinical diagnostic and management characteristics of double thyroglossal duct cyst (TDC) cases. Seventy-eight patients diagnosed with TDCs who were admitted to the inpatient ward of the Department of Otolaryngology, Dalian Central Municipal Hospital from June 2008 to October 2021 were included in the study. Ultimately, 67 of these patients were diagnosed with single TDCs and 11 patients with double TDCs. Each patient underwent computed tomography and color doppler ultrasound imaging of their neck masses, thyroid color doppler ultrasound imaging, and surgical cyst removal through the classic Sistrunk procedure. All surgically excised specimens were sent to the pathology lab for examination and were confirmed to contain TDCs. Two of the 67 patients with single TDCs experienced postoperative complications related to infections within the operative area, whereas no patients with double TDCs experienced postoperative infection, excessive bleeding, or other surgical complications. All cases were followed up for 1 to 3 years after surgery with no cyst recurrence observed. Double TDCs may present on physical examination as unilateral neck masses that interfere with tongue extension and movement and swallowing that can be identified using imaging methods. Correct clinical diagnosis and complete surgical removal of cysts are key measures for ensuring successful treatment outcomes for patients with TDCs.

Rh-Catalyzed Sequential Asymmetric Hydrogenations of 3-Amino-4-Chromones Via an Unusual Dynamic Kinetic Resolution Process.

Rh-catalyzed sequential asymmetric hydrogenations of 3-amino-4-chromones have been achieved for the first time via an unprecedented dynamic kinetic resolution under neutral conditions, providing (S,R)-3-amino-4-chromanols in high yields (up to 98%) with excellent enantio- and diastereoselectivities (up to 99.9% ee and 20:1 dr). The mechanistic studies based on control experiments and density functional theory (DFT) calculations suggest that the dynamic kinetic resolution process for the intermediate enantiomers generated in the first hydrogenation step proceeded via a stereomutation (or called chiral assimilation) pathway from an undesired enantiomer to the desired enantiomer rather than via traditional racemization of the undesired enantiomer. The protocol can be performed on a gram scale with a relatively low catalyst loading and offers a practical and convenient pathway for synthesizing a series of bioactive chromanols and their derivatives.

Whole exome sequencing in patients with Williams-Beuren syndrome followed by disease modeling in mice points to four novel pathways that may modify stenosis risk.

Supravalvular aortic stenosis (SVAS) is a narrowing of the aorta caused by elastin (ELN) haploinsufficiency. SVAS severity varies among patients with Williams-Beuren syndrome (WBS), a rare disorder that removes one copy of ELN and 25-27 other genes. Twenty percent of children with WBS require one or more invasive and often risky procedures to correct the defect while 30% have no appreciable stenosis, despite sharing the same basic genetic lesion. There is no known medical therapy. Consequently, identifying genes that modify SVAS offers the potential for novel modifier-based therapeutics. To improve statistical power in our rare-disease cohort (N = 104 exomes), we utilized extreme-phenotype cohorting, functional variant filtration and pathway-based analysis. Gene set enrichment analysis of exome-wide association data identified increased adaptive immune system variant burden among genes associated with SVAS severity. Additional enrichment, using only potentially pathogenic variants known to differ in frequency between the extreme phenotype subsets, identified significant association of SVAS severity with not only immune pathway genes, but also genes involved with the extracellular matrix, G protein-coupled receptor signaling and lipid metabolism using both SKAT-O and RQTest. Complementary studies in Eln+/-; Rag1-/- mice, which lack a functional adaptive immune system, showed improvement in cardiovascular features of ELN insufficiency. Similarly, studies in mixed background Eln+/- mice confirmed that variations in genes that increase elastic fiber deposition also had positive impact on aortic caliber. By using tools to improve statistical power in combination with orthogonal analyses in mice, we detected four main pathways that contribute to SVAS risk.

Genome-wide survey and expression analysis of GRAS transcription factor family in sweetpotato provides insights into their potential roles in stress response.

BACKGROUND: The plant-specific GRAS transcription factors play pivotal roles in various adverse environmental conditions. Numerous GRAS genes have been explored and characterized in different plants, however, comprehensive survey on GRASs in sweetpotato is lagging. RESULTS: In this study, 72 putative sweetpotato IbGRAS genes with uneven distribution were isolated on 15 chromosomes and classified into 12 subfamilies supported by gene structures and motif compositions. Moreover, both tandem duplication and segmental duplication events played critical roles in the expansion of sweetpotato GRAS genes, and the collinearity between IbGRAS genes and the related orthologs from nine other plants further depicted evolutionary insights into GRAS gene family. RNA-seq analysis under salt stress and qRT-PCR detection of 12 selected IbGRAS genes demonstrated their significant and varying inductions under multiple abiotic stresses (salt, drought, heat and cold) and hormone treatments (ABA, ACC and JA). Consistently, the promoter regions of IbGRAS genes harbored a series of stress- and hormone-associated cis-acting elements. Among them, IbGRAS71, the potential candidate for breeding tolerant plants, was characterized as having transactivation activity in yeasts, while IbGRAS-2/-4/-9 did not. Moreover, a complex interaction relationship between IbGRASs was observed through the interaction network analysis and yeast two-hybrid assays. CONCLUSIONS: Our results laid a foundation for further functional identifications of IbGRAS genes, and multiple members may serve as potential regulators for molecular breeding of tolerant sweetpotato.

Frequency of QTc Interval Prolongation in Children and Adults with Williams Syndrome.

QTc prolongation (≥ 460 ms), according to Bazett formula (QTcB), has been identified to be increased in Williams syndrome (WS) and suggested as a potential cause of increased risk of sudden cardiac death. The Bazett formula tends to overestimate QTc in higher heart rates. We performed a retrospective chart review of WS patients with ≥ 1 electrocardiogram (EKG) with sinus rhythm, no evidence of bundle branch blocks, and measurable intervals. A total of 280 EKGs from 147 patients with WS were analyzed and 123 EKGs from 123 controls. The QTc was calculated using Bazett formula. The average QTcB for individuals with WS and controls was 444 ± 24 ms and 417 ± 26 ms, respectively (p < 0.001). In our WS cohort 34.4% had at least 1 EKG with a QTcB ≥ 460 ms. The mean heart rate (HR) from patients with WS was significantly higher than controls (96 bpm vs 76 bpm, p < 0.001). Linear regression showed that HR contributed 27% to QTcB prolongation in the patients with WS. Patients with WS have a mean QTcB in the normal range but higher than controls, and a higher than expected frequency of QTc ≥ 460 ms compared to the general population. HR is also higher in WS and contributes modestly to the WS QTcB prolongation. Future studies are needed to assess if these findings contribute risk to sudden cardiac death but in the interim we recommend routine EKG testing, especially when starting QTc prolonging medications.

Automatic Femoral Deformity Analysis Based on the Constrained Local Models and Hough Forest.

Clinically, Taylor spatial frame (TSF) is usually used to correct femoral deformity. The first step in correction is to analyze skeletal deformities and measure the center of rotation of angulation (CORA). Since the above work needs to be done manually, the doctor's workload is heavy. Therefore, an automatic femoral deformity analysis system was proposed. Firstly, the Hough forest and constrained local models were trained on the femur image set. Then, the position and size of the femur in the X-ray image were detected by the trained Hough forest. Furthermore, the position and size were served as the initial values of the trained constrained local models to fit the femoral contour. Finally, the anatomical axis line of the proximal femur and the anatomical axis line of the distal femur could be drawn according to the fitting results. According to these lines, CORA can be found. Compared with manual measurement by doctors, the average error of the hip joint orientation line was 1.7°, the standard deviation was 1.75, the average error of the anatomic axis line of the proximal femur was 2.9°, and the standard deviation was 3.57. The automatic femoral deformity analysis system meets the accuracy requirements of orthopedics and can significantly reduce the workload of doctors.

Copper-Binding Domain Variation in a Novel Murine Lysyl Oxidase Model Produces Structurally Inferior Aortic Elastic Fibers Whose Failure Is Modified by Age, Sex, and Blood Pressure.

Lysyl oxidase (LOX) is a copper-binding enzyme that cross-links elastin and collagen. The dominant LOX variation contributes to familial thoracic aortic aneurysm. Previously reported murine Lox mutants had a mild phenotype and did not dilate without drug-induced provocation. Here, we present a new, more severe mutant, Loxb2b370.2Clo (c.G854T; p.Cys285Phe), whose mutation falls just N-terminal to the copper-binding domain. Unlike the other mutants, the C285F Lox protein was stably produced/secreted, and male C57Bl/6J Lox+/C285F mice exhibit increased systolic blood pressure (BP; p < 0.05) and reduced caliber aortas (p < 0.01 at 100mmHg) at 3 months that independently dilate by 6 months (p < 0.0001). Multimodal imaging reveals markedly irregular elastic sheets in the mutant (p = 2.8 × 10−8 for breaks by histology) that become increasingly disrupted with age (p < 0.05) and breeding into a high BP background (p = 6.8 × 10−4). Aortic dilation was amplified in males vs. females (p < 0.0001 at 100mmHg) and ameliorated by castration. The transcriptome of young Lox mutants showed alteration in dexamethasone (p = 9.83 × 10−30) and TGFß-responsive genes (p = 7.42 × 10−29), and aortas from older C57Bl/6J Lox+/C285F mice showed both enhanced susceptibility to elastase (p < 0.01 by ANOVA) and increased deposition of aggrecan (p < 0.05). These findings suggest that the secreted Lox+/C285F mutants produce dysfunctional elastic fibers that show increased susceptibility to proteolytic damage. Over time, the progressive weakening of the connective tissue, modified by sex and blood pressure, leads to worsening aortic disease.

A bacterial F-box effector suppresses SAR immunity through mediating the proteasomal degradation of OsTrxh2 in rice.

Plant bacterial pathogens usually cause diseases by secreting and translocating numerous virulence effectors into host cells and suppressing various host immunity pathways. It has been demonstrated that the extensive ubiquitin systems of host cells are frequently interfered with or hijacked by numerous pathogenic bacteria, through various strategies. Some type-III secretion system (T3SS) effectors of plant pathogens have been demonstrated to impersonate the F-box protein (FBP) component of the SKP1/CUL1/F-box (SCF) E3 ubiquitin system for their own benefit. Although numerous putative eukaryotic-like F-box effectors have been screened for different bacterial pathogens by bioinformatics analyses, the targets of most F-box effectors in host immune systems remain unknown. Here, we show that XopI, a putative F-box effector of African Xoo (Xanthomonas oryzae pv. oryzae) strain BAI3, strongly inhibits the host's OsNPR1-dependent resistance to Xoo. The xopI knockout mutant displays lower virulence in Oryza sativa (rice) than BAI3. Mechanistically, we identify a thioredoxin protein, OsTrxh2, as an XopI-interacting protein in rice. Although OsTrxh2 positively regulates rice immunity by catalyzing the dissociation of OsNPR1 into monomers in rice, the XopI effector serves as an F-box adapter to form an OSK1-XopI-OsTrxh2 interaction complex, and further disrupts OsNPR1-mediated resistance through proteasomal degradation of OsTrxh2. Our results indicate that XopI targets OsTrxh2 and further represses OsNPR1-dependent signaling, thereby subverting systemic acquired resistance (SAR) immunity in rice.

Method of space object detection by wide field of view telescope based on its following error.

Space objects and stars appear similar in images acquired by the wide field of view (FOV) survey telescope. This work investigates a unique property of the telescope observing a space object in satellite tracking mode, namely that the azimuth and altitude angles of the object and those of the optical axis of the telescope vary, in theory, in the same way. Based on this property we derive that the movement distance of the object between the two adjacent frames is minimal compared to the distance of the star. With this conclusion, it is possible to detect the object from a large number of background stars. To improve the robustness of the detection, the set of candidate objects is created. Finally, a clustering algorithm is employed to successfully extract the motion trajectory of the object. Unlike traditional detection methods or techniques based on image processing and analysis, our proposed detection is closely related to the parameters of the trajectory-following performance, which provides a more reliable basis for improving the detection rate. The feasibility and accuracy of the algorithm was verified by the 1.2-meter wide FOV survey telescope at the Jilin base of the Changchun observatory, with a detection rate of over 98%. The test results indicate that the method can satisfy the demand for detecting the object in an open-loop tracking. If the detection method is implemented in hardware, it can detect the object in a closed-loop tracking. As a result, it will have a wider scope for applications.

Factors influencing the reference interval of thyroid-stimulating hormone in healthy adults: A systematic review and meta-analysis.

BACKGROUND: Many studies have reported that the thyroid-stimulating hormone (TSH) reference interval is susceptible to external factors, such as age, sex, race, region and iodine intake. However, no meta-analysis has comprehensively explored the effect of these factors on the TSH reference interval. METHODS: Articles published from January 1960 to January 2020 were searched in PubMed, Embase, Cochrane, Scopus, Medline English databases and CNKI, WanFang and CQVIP Chinese databases. In total, 19 studies were ultimately included. All data were analysed using Review Manager 5.3, STATA 16.0 software, GraphPad Prism 8.0 and Microsoft Excel 2010 to draw the TSH concentration curve. RESULTS: The TSH reference interval was significantly influenced by sex and age. The mean of TSH concentration in females was 0.27 mIU/L higher than that in males. Reference interval of TSH is divided into 20-59 years old and >60 years old age groups in males, and 20-39 years old and >40 years old age groups in females. Regardless of sex, TSH concentrations all increase with age. In iodine-deficient areas, TSH reference intervals were generally lower than those in iodine-sufficient or iodine-excessive areas. The TSH reference interval in Asia and North American countries was generally higher than that in most European countries. In the subgroup analyses of sample size, region and assay methods and manufacturers, the between-group differences were significant. CONCLUSION: The TSH reference interval was significantly influenced by sex, age, iodine intake, sample size, region, and assay methods and manufacturers, but other factors should not be ignored. Therefore, it is necessary for each laboratory to validate an appropriate TSH reference interval based on local conditions.

Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function.

Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a-Stat5b double knockin (DKI) N-domain mutant mice in which STAT5 proteins form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined dimer versus tetramer consensus motifs. Whereas Stat5-deficient mice exhibited perinatal lethality, DKI mice were viable; thus, STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4(+)CD25(+) T cells, NK cells, and CD8(+) T cells, with impaired cytokine-induced and homeostatic proliferation of CD8(+) T cells. Moreover, DKI CD8(+) T cell proliferation after viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is critical for cytokine responses and normal immune function, establishing a critical role for STAT5 tetramerization in vivo.

Cobalt-doped bioceramic scaffolds fabricated by 3D printing show enhanced osteogenic and angiogenic properties for bone repair.

BACKGROUND: The bone regeneration of artificial bone grafts is still in need of a breakthrough to improve the processes of bone defect repair. Artificial bone grafts should be modified to enable angiogenesis and thus improve osteogenesis. We have previously revealed that crystalline Ca10Li(PO4)7 (CLP) possesses higher compressive strength and better biocompatibility than that of pure beta-tricalcium phosphate (ß-TCP). In this work, we explored the possibility of cobalt (Co), known for mimicking hypoxia, doped into CLP to promote osteogenesis and angiogenesis. METHODS: We designed and manufactured porous scaffolds by doping CLP with various concentrations of Co (0, 0.1, 0.25, 0.5, and 1 mol%) and using 3D printing techniques. The crystal phase, surface morphology, compressive strength, in vitro degradation, and mineralization properties of Co-doped and -undoped CLP scaffolds were investigated. Next, we investigated the biocompatibility and effects of Co-doped and -undoped samples on osteogenic and angiogenic properties in vitro and on bone regeneration in rat cranium defects. RESULTS: With increasing Co-doping level, the compressive strength of Co-doped CLP scaffolds decreased in comparison with that of undoped CLP scaffolds, especially when the Co-doping concentration increased to 1 mol%. Co-doped CLP scaffolds possessed excellent degradation properties compared with those of undoped CLP scaffolds. The (0.1, 0.25, 0.5 mol%) Co-doped CLP scaffolds had mineralization properties similar to those of undoped CLP scaffolds, whereas the 1 mol% Co-doped CLP scaffolds shown no mineralization changes. Furthermore, compared with undoped scaffolds, Co-doped CLP scaffolds possessed excellent biocompatibility and prominent osteogenic and angiogenic properties in vitro, notably when the doping concentration was 0.25 mol%. After 8 weeks of implantation, 0.25 mol% Co-doped scaffolds had markedly enhanced bone regeneration at the defect site compared with that of the undoped scaffold. CONCLUSION: In summary, CLP doped with 0.25 mol% Co2+ ions is a prospective method to enhance osteogenic and angiogenic properties, thus promoting bone regeneration in bone defect repair.

Rhodium-Catalyzed Asymmetric Hydrogenation of 3-Benzoylaminocoumarins for the Synthesis of Chiral 3-Amino Dihydrocoumarins.

An asymmetric hydrogenation of 3-benzoylaminocoumarins was achieved for the first time using our BridgePhos-Rh catalytic system, providing chiral 3-amino dihydrocoumarins in high yields (up to 98 %) and with excellent enantioselectivities (up to 99.7 % ee). The relationship between the enantioselectivities of the hydrogenations and the dihedral angles and the resulting π-π stacking effects of the BridgePhos-Rh complexes, which were determined by X-ray diffraction analysis, are discussed. The corresponding hydrogenated products allow for many transformations, providing several chiral skeletons with important physiological and pharmacological activities.

Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26-28 genes. An estimated 2-5% of patients have "atypical" deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature. Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p = .001), with higher (more impaired) scores for social motivation (p = .005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation.

Activation of Th1 Immunity within the Tumor Microenvironment Is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia.

Immune stimulation contributes to lenalidomide's antitumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood, and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T cell function in vitro. Whether T cell activation is required for clinical response to lenalidomide remains unclear. In this study, we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with antitumor response. Within days of starting lenalidomide, T cells increased in the tumor microenvironment and showed Th1-type polarization. Gene expression profiling of pretreatment and on-treatment lymph node biopsy specimens revealed upregulation of IFN-γ and many of its target genes in response to lenalidomide. The IFN-γ-mediated Th1 response was limited to patients achieving a clinical response defined by a reduction in lymphadenopathy. Deep sequencing of TCR genes revealed decreasing diversity of the T cell repertoire and an expansion of select clonotypes in responders. To validate our observations, we stimulated T cells and CLL cells with lenalidomide in culture and detected lenalidomide-dependent increases in T cell proliferation. Taken together, our data demonstrate that lenalidomide induced Th1 immunity in the lymph node that is associated with clinical response.