Bortezomib in relapsed/refractory immune thrombotic thrombocytopenic purpura: A single-centre retrospective cohort and systematic literature review.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX), corticosteroids, caplacizumab and rituximab. In relapsed and refractory cases despite initial treatments, further immune-modulating therapy includes the proteasome inhibitor, bortezomib. Evidence for bortezomib in this setting is limited to case reports and case series. We report our experience and perform a systematic review of the literature. We identified 21 publications with 28 unique patients in addition to our cohort of eight patients treated with bortezomib. The median age of patients was 44 years (IQR: 27-53) and 69% female. They were usually in an initial, refractory presentation of iTTP where they had received PLEX, corticosteroids, rituximab and another line of therapy. After bortezomib administration, 72% of patients had a complete response, with 85% maintaining a durable response without relapse at the last follow-up.

A massive, dead disk galaxy in the early Universe.

At redshift z = 2, when the Universe was just three billion years old, half of the most massive galaxies were extremely compact and had already exhausted their fuel for star formation. It is believed that they were formed in intense nuclear starbursts and that they ultimately grew into the most massive local elliptical galaxies seen today, through mergers with minor companions, but validating this picture requires higher-resolution observations of their centres than is currently possible. Magnification from gravitational lensing offers an opportunity to resolve the inner regions of galaxies. Here we report an analysis of the stellar populations and kinematics of a lensed z = 2.1478 compact galaxy, which-surprisingly-turns out to be a fast-spinning, rotationally supported disk galaxy. Its stars must have formed in a disk, rather than in a merger-driven nuclear starburst. The galaxy was probably fed by streams of cold gas, which were able to penetrate the hot halo gas until they were cut off by shock heating from the dark matter halo. This result confirms previous indirect indications that the first galaxies to cease star formation must have gone through major changes not just in their structure, but also in their kinematics, to evolve into present-day elliptical galaxies.

Leave No Trace? Ecological and anthropogenic determinants of antibiotic resistant bacteria in a recreational alpine environment.

Antibiotic resistant bacteria (ARB) have been detected in remote environments, but the degree to which their presence is due to anthropogenic contamination remains unclear. Here, anthropogenic and ecological determinants of ARB were characterized in remote and highly visited areas of Rocky Mountain National Park in the United States. Soil and water samples were collected from 29 sites once a month for three months and measured for bacteria resistant to seven antibiotics with flow cytometry. A novel index of the likelihood of human presence (HPI) was generated for estimating human impact on ARB abundance. The HPI accounted for 44% of variation in ARB abundance in water samples (p < 0.0001) and 51% of variation in soil samples (p < 0.00001). Human presence index was illustrated as a reliable predictor of ARB abundance despite a tendency to underpredict at higher levels of human impact. Ecological determinants such as temperature, elevation, slope, and aspect were also found to be significantly associated with ARB abundance. These findings suggest that human presence drives the abundance of ARB in Rocky Mountain National Park, but ecological variables play a significant role in their presence and dispersal.

Ataxin-1 regulates B cell function and the severity of autoimmune experimental encephalomyelitis.

Ataxin-1 (ATXN1) is a ubiquitous polyglutamine protein expressed primarily in the nucleus where it binds chromatin and functions as a transcriptional repressor. Mutant forms of ataxin-1 containing expanded glutamine stretches cause the movement disorder spinocerebellar ataxia type 1 (SCA1) through a toxic gain-of-function mechanism in the cerebellum. Conversely, ATXN1 loss-of-function is implicated in cancer development and Alzheimer's disease (AD) pathogenesis. ATXN1 was recently nominated as a susceptibility locus for multiple sclerosis (MS). Here, we show that Atxn1-null mice develop a more severe experimental autoimmune encephalomyelitis (EAE) course compared to wildtype mice. The aggravated phenotype is mediated by increased T helper type 1 (Th1) cell polarization, which in turn results from the dysregulation of B cell activity. Ataxin-1 ablation in B cells leads to aberrant expression of key costimulatory molecules involved in proinflammatory T cell differentiation, including cluster of differentiation (CD)44 and CD80. In addition, comprehensive phosphoflow cytometry and transcriptional profiling link the exaggerated proliferation of ataxin-1 deficient B cells to the activation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) pathways. Lastly, selective deletion of the physiological binding partner capicua (CIC) demonstrates the importance of ATXN1 native interactions for correct B cell functioning. Altogether, we report a immunomodulatory role for ataxin-1 and provide a functional description of the ATXN1 locus genetic association with MS risk.

Immature Platelet Fraction as a Biomarker for Disease Severity in Pediatric Respiratory Coronavirus Disease 2019.

In this retrospective single-institution cohort study of 113 hospitalized pediatric patients with respiratory coronavirus disease 2019, those admitted to the intensive care unit or requiring mechanical ventilation had significantly higher immature platelet fractions than those who did not require intensive care unit-level care or ventilation. Immature platelet fraction may be an accessible biomarker for disease severity in pediatric respiratory coronavirus disease 2019.

Comparison of Prasugrel and Ticagrelor for Patients with Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

INTRODUCTION: There have been inconsistent data on the direct comparison of prasugrel and ticagrelor. This meta-analysis was conducted to summarize the current available evidence. METHODS: We performed a meta-analysis (PROSPERO-registered CRD42020166810) of randomized trials up to February 2020 that compared prasugrel and ticagrelor in acute coronary syndrome with respect to the composite endpoint of myocardial infarction (MI), stroke, or cardiovascular death and secondary endpoints including MI, stroke, cardiovascular death, major bleeding (Bleeding Academic Research Consortium (BARC) type 2 or above), stent thrombosis, all-cause death, and other safety outcomes. RESULTS: Of the 11 eligible RCTs with 6,098 patients randomized to prasugrel (n = 3,050) or ticagrelor (n = 3,048), 180 and 207 had the composite endpoint events in the prasugrel arm and the ticagrelor arm, respectively, over a weighted mean follow-up period of 11 ± 2 months. Compared with prasugrel, the ticagrelor group had similar risk in the primary composite endpoint (risk ratio [RR] = 1.17; 95% CI = 0.96-1.42; p = 0.12, I2 = 0%). Compared to prasugrel, there was no significant difference associated with the ticagrelor groups with respect to stroke (RR = 1.05; 95% CI = 0.66-1.67; p = 0.84, I2 = 0%), cardiovascular death (RR = 1.01; 95% CI = 0.75-1.36; p = 0.95, I2 = 0%), BARC type 2 or above bleeding (RR = 1.16; 95% CI = 0.89-1.52; p = 0.26, I2 = 0%), stent thrombosis (RR = 1.58; 95% CI = 0.90-2.76; p = 0.11, I2 = 0%), and all-cause death (RR = 1.10; 95% CI = 0.86-1.43; p = 0.45, I2 = 0%) except MI (RR = 1.38; 95% CI = 1.05-1.81; p = 0.02, I2 = 0%) Conclusion: Compared with prasugrel, ticagrelor did not reduce the primary composite endpoint of MI, stroke, and cardiovascular death at a weighted mean follow-up of 11 months. There was no significant difference between the secondary outcomes except MI.

Non-innocent ligand flavone and curcumin inspired ruthenium photosensitizers for solar energy conversion.

A series of ruthenium photosensitizers incorporating a ß-diketonate non-innocent ligand were synthesized, characterized, and implemented in dye-sensitized solar cells. Electrochemical studies exhibited well behaved reversible oxidations and reductions for all ß-diketonate complexes. The acac- and Ph2acac- based photosensitizers possess limited delocalization across the ligand π*-manifold, which is significant for exhibition of respectable power conversion efficiencies in a dye-sensitized solar cell (DSC) device. As the π-orbital network was extended on the flavone and curcumin inspired NILs, increased molar absorptivity was observed, however this ultimately proved detrimental to DSC performance consistent with exhibition of negligible photocurrent.

Complete ADAMTS13 remission in a patient with refractory autoimmune-mediated thrombotic thrombocytopenic purpura after infliximab.

Autoimmune thrombotic thrombocytopenic purpura (aTTP) is caused by autoantibodies to the von Willebrand Factor cleaving enzyme, ADAMTS13. Despite recent advances in the treatment of acute aTTP, relapse rates remain high. Guidance for the treatment of patients in clinical remission but with persistent severe ADAMTS13 deficiency who fail to respond to rituximab remains unclear. We report a case of a 29-year-old man diagnosed with aTTP at the age of 11. Over a period of 18 years, he had five clinical relapses with persistent severe ADAMTS13 deficiency (<10%) and presence of autoantibodies during clinical remissions despite immunosuppressive therapy with rituximab, bortezomib and azathioprine. While in a clinical remission, he was diagnosed with Crohn's disease and initially treated with adalimumab. When he subsequently developed antibodies to adalimumab, he was transitioned to infliximab. ADAMTS13 activity increased to 24% by 2 months of infliximab induction, and four months later the ADAMTS13 activity improved to 42%. This case demonstrates the importance of managing concurrent inflammatory disorders and suggests that TNF may play a role in autoantibody development and ADAMTS13 depletion.

The Use of Interlocking Polyetheretherketone (PEEK) Patient-Specific Facial Implants in the Treatment of Facial Deformities. A Retrospective Review of Ten Patients.

PURPOSE: Polyetheretherketone (PEEK) is a versatile biocompatible material with a wide variety of clinical applications. Multiple-piece 3-dimensionally milled interlocking PEEK patient-specific implants are used in cases with restricted access or around vital structures. The interlocking joints reduce the number of fixation screws required by converting the multiple segments into 1 single implant. Stability of such joints is of paramount importance to prevent complications such as infection and implant extrusion. This retrospective study evaluates the clinical outcomes in the use of multiple-piece 3-dimensionally milled interlocking PEEK patient-specific implants as a treatment for various congenital and acquired facial deformities. METHODS: Patients' records and clinical interviews were retrospectively reviewed. RESULTS: A total of 10 patients were included; 6 of them (60%) were men. A planning cone beam scan (90%) or computed tomography scan (10%) were obtained following a standard protocol. All treatments were performed by a single surgeon, following a standardized approach. The follow-up time ranged from 11 to 61 months (mean = 37.1 months). No implant exposure, extrusion or removal were reported. Three patients (30%) experienced complications. Recurrent edema was observed in 1 patient (10%), another patient (10%) experienced bilateral mental nerve paresthesia, and the third patient (10%) had recurrent sinusitis, which was successfully treated with functional endoscopic sinus surgery without removing the implant. CONCLUSION: Within the limitation of this study, 3-dimensionally milled interlocking PEEK patient-specific implants are safe, predictable, potentially save operative time, and readily adjustable. Extra stability and antislippage mechanism can be achieved by using the interlocking joint. Further studies on a larger cohort of patients is needed to confirm these results.

Pathologic staging changes in oral cavity squamous cell carcinoma: Stage migration and implications for adjuvant treatment.

BACKGROUND: The eighth edition of the AJCC Cancer Staging Manual (AJCC 8) incorporates depth of invasion (DOI) into the pathologic tumor (pT) classification and pathologic extranodal extension (pENE) into the pathologic nodal (pN) classification for oral cavity squamous cell carcinoma (OCSCC). This study evaluated the incidence and prognostic importance of stage migration as a result of these changes in the AJCC 8 staging system. METHODS: From the National Cancer Database, cohorts were identified from patients with OCSCC undergoing definitive surgery between 2004 and 2013 for pT (n = 7184), pN (n = 13,627), and pathologic stage (pStage) analysis (n = 5580). RESULTS: DOI and pENE were prognostic in all groups except for pN3 according to the seventh edition of the AJCC Cancer Staging Manual (AJCC 7). Upstaging was seen in 12.4% of patients for the pT classification, in 13.3% for the pN classification, and in 24.8% for the overall pStage grouping. Notably, upstaging led to similar or improved 5-year overall survival (OS) for every AJCC 8 pT/N classification except pStage IVB. Patients with AJCC 7 pT1 tumors that were upstaged to AJCC 8 pT3 tumors had improved OS in comparison with the remainder of the pT3 group (71.7% vs 43.7%; P < .0001). A multivariable analysis of upstaged pT3N0 patients demonstrated a reduced risk of death with the receipt of postoperative radiotherapy (PORT; hazard ratio, 0.56; 95% confidence interval, 0.33-0.95; P = .03). CONCLUSIONS: Upstaging is common in AJCC 8, and patients with upstaged tumors demonstrate improved survival; these factors should be kept in mind when one is interpreting data with the new staging system. PORT may reduce deaths among newly upstaged pT3N0 patients, and further study is needed in this area.

Radiation therapy treatment facility and overall survival in the adjuvant setting for locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Treatment at high-volume surgical facilities (HVSFs) provides a survival benefit for patients with head and neck squamous cell carcinomas (HNSCCs); however, it is unknown what role postoperative radiation therapy (PORT) plays in achieving the improved outcomes. METHODS: From the National Cancer Database, 6844 patients with locally advanced invasive HNSCCs of the oral cavity, oropharynx, larynx, and hypopharynx who underwent definitive surgery with PORT between 2004 and 2013 were identified. HVSFs were those in the top percentile for annual case volume during this period. RESULTS: The median follow-up was 54 months. Compared with a lower volume surgical facility (LVSF), an HVSF improved 5-year overall survival (OS; 57.7% at HVSFs vs 52.5% at LVSFs; P = .0003). Overall, 31.6% of the patients changed their radiation therapy (RT) facility after surgery, with this being more common at HVSFs (39.1% vs 28.9% at LVSFs; P < .001). Among those patients undergoing surgery at an HVSF, remaining at the same facility for RT improved 5-year OS (63.1% vs 49.3% with a facility change; P < .0001). A propensity score-matched cohort of patients treated at HVSFs confirmed the improved 5-year OS when patients remained at the treating HVSF for RT (59.2% vs 50.7% with a facility change; P = .005). In a multivariate analysis, treatment at an HVSF and remaining there for RT resulted in a reduced hazard of death (hazard ratio, 0.81; 95% confidence interval, 0.69-0.94; P = .006). CONCLUSIONS: The survival benefit associated with HVSFs persists only when patients remain at the facility for RT, and this suggests that facility specialization and/or high-volume PORT may assist in driving the OS improvement.

Hyperlactatemia Predicts Citrate Intolerance With Regional Citrate Anticoagulation During Continuous Renal Replacement Therapy.

PURPOSE:: We aim to determine whether hyperlactatemia, which suggests multi-organ dysfunction and impaired organic substrate metabolism, may predict intolerance to regional citrate anticoagulation (RCA) during continuous venovenous hemofiltration (CVVH). METHODS:: We performed a single-center, retrospective observational study in critically ill patients with acute kidney injury or end-stage renal disease and evaluated the association of peak serum lactate levels with citrate intolerance (CI) during the initial 72 hours of RCA-CVVH, defined by serum total-to-ionized calcium >2.5 plus systemic hypocalcemia. RESULTS:: Eighty-eight patients were studied (aged 59 ± 14 years, 66% males, Acute Physiology and Chronic Health Evaluation II: 31 ± 8). Citrate was dosed at median 2.1 mmol/L of blood flow, with citrate load of 30 mmol/h, and CVVH effluent of 43 mL/kg/h. Twenty patients developed CI. Comparing patients with CI versus none, peak lactate levels were 8 (5-11) versus 3 (2-6) mmol/L, calcium replacement was 13 (10-17) versus 11 (8-12) mmol/h, and standard base excess was -4 (-12 to 1) versus 2(-4 to 7) mmol/L, respectively ( P < .05). Citrate intolerance developed in 38%, 44%, and 55%, in patients with peak lactate >4, >6, >7 mmol/L, respectively, versus 7% in those with peak lactate ≤4 mmol/L ( P ≤ .001), despite comparable citrate load and effluent rates across all categories. On multivariate analysis, hyperlactatemia and hyperbilirubinemia predicted CI ( P ≤ .01), which was associated with increasing calcium infusion requirement. Higher peak lactate from >4 to >7 mmol/L predicted CI with graded increase in odds ratio and specificity from 59% to 87%, but the corresponding negative predictive value from 93% to 87%. Area under nonparametric receiver operating characteristic curve for peak lactate and CI was 0.78. CONCLUSION:: Hyperlactatemia predicts CI during RCA-CVVH with reasonable discriminatory performance in critically ill patients. Serum lactate surveillance may help preempt issues with citrate toxicity.

Guanidine-Copper Complex Catalyzed Allylic Borylation for the Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates.

An enantioconvergent synthesis of chiral cyclic allylboronates from racemic allylic bromides was achieved by using a guanidine-copper catalyst. The allylboronates were obtained with high γ/α regioselectivities (up to 99:1) and enantioselectivities (up to 99 % ee), and could be further transformed into diverse functionalized allylic compounds without erosion of optical purity. Experimental and DFT mechanistic studies support an SN 2' borylation process catalyzed by a monodentate guanidine-copper(I) complex that proceeds through a special direct enantioconvergent transformation mechanism.

Engineering of Ruthenium(II) Photosensitizers with Non-Innocent Oxyquinolate and Carboxyamidoquinolate Ligands for Dye-Sensitized Solar Cells.

An alternative approach to replacing the isothiocyantate ligands of the N3 photosensitizer with light-harvesting bidentate ligands is investigated for application in dye-sensitized solar cells (DSSCs). An in-depth theoretical analysis has been applied to investigate the optical and redox properties of four non-innocent ligand platforms, which is then corroborated with experiment. Taking advantage of the 5- and 7-positions of 8-oxyquinolate, or the carboxyaryl ring system of the N-arylcarboxy-8-amidoquinolate ligand, fluorinated aryl substituents are demonstrated as an effective means of tuning complex redox potentials and light-harvesting properties. The non-innocent character, resulting from mixing of both the central metal-dπ and ligand-π manifolds, generates hybrid metal-ligand frontier orbitals. These play a major role by contributing to the redox properties and visible electronic transitions, and promoting an improved power conversion efficiency in a Ru DSSC device featuring non-innocent ligands.

Highly efficient CRISPR/Cas9-mediated TAR cloning of genes and chromosomal loci from complex genomes in yeast.

Transformation-associated recombination (TAR) protocol allowing the selective isolation of full-length genes complete with their distal enhancer regions and entire genomic loci with sizes up to 250 kb from complex genomes in yeast S. cerevisiae has been developed more than a decade ago. However, its wide spread usage has been impeded by a low efficiency (0.5-2%) of chromosomal region capture during yeast transformants which in turn requires a time-consuming screen of hundreds of colonies. Here, we demonstrate that pre-treatment of genomic DNA with CRISPR-Cas9 nucleases to generate double-strand breaks near the targeted genomic region results in a dramatic increase in the fraction of gene-positive colonies (up to 32%). As only a dozen or less yeast transformants need to be screened to obtain a clone with the desired chromosomal region, extensive experience with yeast is no longer required. A TAR-CRISPR protocol may help to create a bank of human genes, each represented by a genomic copy containing its native regulatory elements, that would lead to a significant advance in functional, structural and comparative genomics, in diagnostics, gene replacement, generation of animal models for human diseases and has a potential for gene therapy.

Generation of a conditionally self-eliminating HAC gene delivery vector through incorporation of a tTAVP64 expression cassette.

Human artificial chromosome (HAC)-based vectors represent an alternative technology for gene delivery and expression with a potential to overcome the problems caused by virus-based vectors. The recently developed alphoid(tetO)-HAC has an advantage over other HAC vectors because it can be easily eliminated from cells by inactivation of the HAC kinetochore via binding of chromatin modifiers, tTA or tTS, to its centromeric tetO sequences. This provides a unique control for phenotypes induced by genes loaded into the HAC. The alphoid(tetO)-HAC elimination is highly efficient when a high level of chromatin modifiers as tetR fusion proteins is achieved following transfection of cells by a retrovirus vector. However, such vectors are potentially mutagenic and might want to be avoided under some circumstances. Here, we describe a novel system that allows verification of phenotypic changes attributed to expression of genes from the HAC without a transfection step. We demonstrated that a single copy of tTA(VP64) carrying four tandem repeats of the VP16 domain constitutively expressed from the HAC is capable to generate chromatin changes in the HAC kinetochore that are not compatible with its function. To adopt the alphoid(tetO)-HAC for routine gene function studies, we constructed a new TAR-BRV- tTA(VP64) cloning vector that allows a selective isolation of a gene of interest from genomic DNA in yeast followed by its direct transfer to bacterial cells and subsequent loading into the loxP site of the alphoid(tetO)-HAC in hamster CHO cells from where the HAC may be MMCT-transferred to the recipient human cells.

Kinetochore assembly and heterochromatin formation occur autonomously in Schizosaccharomyces pombe.

Kinetochores in multicellular eukaryotes are usually associated with heterochromatin. Whether this heterochromatin simply promotes the cohesion necessary for accurate chromosome segregation at cell division or whether it also has a role in kinetochore assembly is unclear. Schizosaccharomyces pombe is an important experimental system for investigating centromere function, but all of the previous work with this species has exploited a single strain or its derivatives. The laboratory strain and most other S. pombe strains contain three chromosomes, but one recently discovered strain, CBS 2777, contains four. We show that the genome of CBS 2777 is related to that of the laboratory strain by a complex chromosome rearrangement. As a result, two of the kinetochores in CBS 2777 contain the central core sequences present in the laboratory strain centromeres, but lack adjacent heterochromatin. The closest block of heterochromatin to these rearranged kinetochores is ∼100 kb away at new telomeres. Despite lacking large amounts of adjacent heterochromatin, the rearranged kinetochores bind CENP-A(Cnp1) and CENP-C(Cnp3) in similar quantities and with similar specificities as those of the laboratory strain. The simplest interpretation of this result is that constitutive kinetochore assembly and heterochromatin formation occur autonomously.

Probing the Noninnocent π-Bonding Influence of N-Carboxyamidoquinolate Ligands on the Light Harvesting and Redox Properties of Ruthenium Polypyridyl Complexes.

Electronic and photophysical characterization is presented for a series of bis-heteroleptic [Ru(bpy)2(R-CAQN)](+) complexes where CAQN is a bidentate N-(carboxyaryl)amidoquinolate ligand and the aryl substituent R = p-tolyl, p-fluorobenzene, p-trifluoromethylbenzene, 3,5-bis(trifluoromethyl)benzene, or 4-methoxy-2,3,5,6-tetrafluorobenzene. Characterized by a strong noninnocent Ru(dπ)-CAQN(π) bonding interaction, density functional theory (DFT) analysis is used to estimate the contribution of both atomic Ru(dπ) and ligand CAQN(π) manifolds to the frontier molecular orbitals of these complexes. UV-vis absorption and emission studies are presented where the noninnocent Ru(dπ)-CAQN(π) bonding scheme plays a major role in defining complex electronic and photophysical properties. Oxidation potentials are tuned over a range of 0.92 V with respect to the [Ru(bpy)3](2+) reference system, hereafter referred to as 1(2+), by varying the degree of R-CAQN fluorination while maintaining consistently strong and panchromatic visible absorption properties. Electron paramagnetic resonance (EPR) spectroscopy is employed to experimentally map delocalization of the unpaired electron/electron-hole within the delocalized Ru(dπ)-CAQN(π) singly occupied valence molecular orbital of the one-electron oxidized complexes. EPR data is complemented experimentally by UV-vis-NIR spectroelectrochemistry, and computationally by molecular orbital Mulliken contributions and spin-density analysis. It is ultimately demonstrated that the CAQN ligand framework provides a simple yet broad synthetic platform in the design of redox-active transition metal chromophores with a range of electronic and spectroscopic characteristics hinting at the diversity and potential of these complexes toward photochemical and catalytic applications.

A portable BRCA1-HAC (human artificial chromosome) module for analysis of BRCA1 tumor suppressor function.

BRCA1 is involved in many disparate cellular functions, including DNA damage repair, cell-cycle checkpoint activation, gene transcriptional regulation, DNA replication, centrosome function and others. The majority of evidence strongly favors the maintenance of genomic integrity as a principal tumor suppressor activity of BRCA1. At the same time some functional aspects of BRCA1 are not fully understood. Here, a HAC (human artificial chromosome) module with a regulated centromere was constructed for delivery and expression of the 90 kb genomic copy of the BRCA1 gene into BRCA1-deficient human cells. A battery of functional tests was carried out to demonstrate functionality of the exogenous BRCA1. In separate experiments, we investigated the role of BRCA1 in maintenance of heterochromatin integrity within a human functional kinetochore. We demonstrated that BRCA1 deficiency results in a specific activation of transcription of higher-order alpha-satellite repeats (HORs) assembled into heterochromatin domains flanking the kinetochore. At the same time no detectable elevation of transcription was observed within HORs assembled into centrochromatin domains. Thus, we demonstrated a link between BRCA1 deficiency and kinetochore dysfunction and extended previous observations that BRCA1 is required to silence transcription in heterochromatin in specific genomic loci. This supports the hypothesis that epigenetic alterations of the kinetochore initiated in the absence of BRCA1 may contribute to cellular transformation.