Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation.

Inflammatory and oncogenic signaling converge in disease evolution of BCR-ABL-negative myeloproliferative neoplasms, clonal hematopoietic stem cell disorders characterized by gain-of-function mutation in JAK2 kinase (JAK2V617F), with highest prevalence in patients with polycythemia vera (PV). Despite the high risk, DNA-damaging inflammatory microenvironment, PV progenitors tend to preserve their genomic stability over decades until their progression to post-PV myelofibrosis/acute myeloid leukemia. Using induced pluripotent stem cells-derived CD34+ progenitor-enriched cultures from JAK2V617F+ PV patient and from JAK2 wild-type healthy control, CRISPR-modified HEL cells and patients' bone marrow sections from different disease stages, we demonstrate that JAK2V617F induces an intrinsic IFNγ- and NF-κB-associated inflammatory program, while suppressing inflammation-evoked DNA damage both in vitro and in vivo. We show that cells with JAK2V617F tightly regulate levels of inflammatory cytokines-induced reactive oxygen species, do not fully activate the ATM/p53/p21waf1 checkpoint and p38/JNK MAPK stress pathway signaling when exposed to inflammatory cytokines, suppress DNA single-strand break repair genes' expression yet overexpress the dual-specificity phosphatase (DUSP) 1. RNAi-mediated knock-down and pharmacological inhibition of DUSP1, involved in p38/JNK deactivation, in HEL cells reveals growth addiction to DUSP1, consistent with enhanced DNA damage response and apoptosis in DUSP1-inhibited parental JAK2V617F+ cells, but not in CRISPR-modified JAK2 wild-type cells. Our results indicate that the JAK2V617F+ PV progenitors utilize DUSP1 activity as a protection mechanism against DNA damage accumulation, promoting their proliferation and survival in the inflammatory microenvironment, identifying DUSP1 as a potential therapeutic target in PV.

Tumors overexpressing RNF168 show altered DNA repair and responses to genotoxic treatments, genomic instability and resistance to proteotoxic stress.

Chromatin DNA damage response (DDR) is orchestrated by the E3 ubiquitin ligase ring finger protein 168 (RNF168), resulting in ubiquitin-dependent recruitment of DDR factors and tumor suppressors breast cancer 1 (BRCA1) and p53 binding protein 1 (53BP1). This ubiquitin signaling regulates pathway choice for repair of DNA double-strand breaks (DSB), toxic lesions whose frequency increases during tumorigenesis. Recruitment of 53BP1 curbs DNA end resection, thereby limiting homologous recombination (HR) and directing DSB repair toward error-prone non-homologous end joining (NHEJ). Under cancer-associated ubiquitin starvation conditions reflecting endogenous or treatment-evoked proteotoxic stress, the ubiquitin-dependent accrual of 53BP1 and BRCA1 at the DNA damage sites is attenuated or lost. Challenging this current paradigm, here we identified diverse human cancer cell lines that display 53BP1 recruitment to DSB sites even under proteasome inhibitor-induced proteotoxic stress, that is, under substantial depletion of free ubiquitin. We show that central to this unexpected phenotype is overabundance of RNF168 that enables more efficient exploitation of the residual-free ubiquitin. Cells with elevated RNF168 are more resistant to combined treatment by ionizing radiation and proteasome inhibition, suggesting that such aberrant RNF168-mediated signaling might reflect adaptation to chronic proteotoxic and genotoxic stresses experienced by tumor cells. Moreover, the overabundant RNF168 and the ensuing unorthodox recruitment patterns of 53BP1, RIF1 and REV7 (monitored on laser micro-irradiation-induced DNA damage) shift the DSB repair balance from HR toward NHEJ, a scenario accompanied by enhanced chromosomal instability/micronuclei formation and sensitivity under replication stress-inducing treatments with camptothecin or poly(ADP-ribose) polymerase (PARP) inhibitor. Overall, our data suggest that the deregulated RNF168/53BP1 pathway could promote tumorigenesis by selecting for a more robust, better stress-adapted cancer cell phenotype, through altered DNA repair, fueling genomic instability and tumor heterogeneity. Apart from providing insights into cancer (patho)biology, the elevated RNF168, documented here also by immunohistochemistry on human clinical tumor specimens, may impact responses to standard-of-care and some emerging targeted cancer therapies.

Transcription factor IIH - the protein complex with multiple functions.

Transcription factor IIH (TFIIH) is eukaryotic multi protein complex identified in early 90's. Subsequent years have shown exceptional conservation of its structure from yeast to human. Although initially considered to be exclusively a basal transcription factor responsible for initiation of transcription and transition from initiation to elongation, TFIIH is also important in nucleotide excision repair for opening DNA at the site of a lesion and for recruitment of additional repair factors. Recently it was suggested that intact holocomplex of TFIIH is required for cell cycle regulation. Moreover, mutations in TFIIH subunits lead to three distinct genetic disorders: xeroderma pigmentosum (DNA repair disorder/cancer syndrome), Cockayne syndrome (DNA repair disorder/transcription syndrome/segmental progeria) and trichothiodystrophy (DNA repair disorder/transcription syndrome). This review is focused on the TFIIH structure, its role in transcription, DNA repair and cell cycle regulation and association with some human hereditary disorders.

ECT administration in a patient after craniotomy and gamma knife surgery: a case report and review.

The safe administration of electroconvulsive therapy (ECT) in a man with steroid-induced depression and a history of craniotomy and gamma knife surgery for two separate foci of metastatic laryngeal cancer is reported. This is the first reported case of ECT given to a patient with a history of gamma knife surgery. The literature on ECT administration to patients with brain masses or a history of craniotomy is reviewed. The current case report indicates that with careful medical evaluation, including consultation with neurosurgeons and internal medicine physicians, ECT may be safely administered to this patient population.

The effects of antidepressants on sleep: a review.

Sleep disturbances are a frequent complication of depressive disorders and their treatment. Familiarity with the interaction among sleep, depression, and antidepressant medications may assist the clinician in selecting agents to suit the needs of individual patients. The authors review the current knowledge of changes in sleep architecture associated with particular antidepressant agents and with depressive illness, as well as the theoretical relevance of such changes to the antidepressant effect. Articles for review were found through a Medline search on the terms "polysomnography," "sleep," "antidepressants," and "insomnia" in English-language papers published from 1966 through March 2000. Additional articles were found in the reference lists of relevant papers.

Duodenal-ulcer disease associated with elevated serum pepsinogen I: an inherited autosomal dominant disorder.

To delineate genetic factors involved in the pathogenesis of duodenal ulcer, serum pepsinogen I levels were determined by radioimmunoassay in two large kindreds with multiple members affected with duodenal ulcer. An elevated serum immunoreactive pepsinogen I concentration (greater than 100 ng per milliliter) segregated as an autosomal dominant trait in these families. Furthermore, 10 of 11 patients with clinical ulcer disease in these families had hyperpepsinogenemia. An elevated serum pepsinogen I concentration appears to be a subclinical marker of the ulcer diathesis in families with this autosomal dominant form of peptic-ulcer disease.

HLA-B5 associated with duodenal ulcer.

In a search for further genetic factors contributing to ulcer disease we undertook a study of the frequency of HLA antigens in patients with duodenal ulcer. Seventy-seven male patients (of two races) were typed for the HLA-A and-B loci. Thirteen of the 54 (24%) white males were found to have antigen B5 compared to 10% of controls. These results have a P value of 0.0016 which remains significant even when multiplied by the number of antigens tested (28). These results demonstrate a significant association between duodenal ulcer and HLA antigen B5 in white males, with a relative risk of 2.9, greater than that associated with the combination of blood group O and nonsecretor status.

Far infrared filters for a rocket-borne radiometer.

Low pass far infrared radiation filters with cutoff frequencies in the spectral region of 10-25 cm(-1) were required for a rocket-borne radiometer experiment. The paper describes the theory, fabrication, and laboratory transmission measurements of prototype grid filters investigated in a study prior to the construction of flight filters. Characteristics of the final flight filters are also presented.