BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells.

Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-κB (NF-κB) target genes that undermines the growth and survival of mantle cell lymphoma (MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-κB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior preclinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or -resistant MCL.

Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.

The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

Sickle cell anemia: a review of the dental concerns and a retrospective study of dental and bony changes.

This paper is a review of the medical concerns pertinent to dental care and a preliminary study of dental findings of the sickle cell anemia (SS) patient. The dental characteristics observed in 21 dental patients with SS are described. Radiographic findings included "stepladder" trabeculae pattern (70%), enamel hypomineralization (24%), calcified canals (5%), increased overbite (30-80%), and increased overjet (56%). Comparisons are made with other studies of the sickle cell patient, and the need for further study is suggested.

Oral opening and other selected facial dimensions of children 6 weeks to 36 months of age.

Four hundred twenty-two children (Caucasians, Asians, and blacks) aged 6 weeks to 36 months were recruited. Five measurements (incisal edge distance, alveolar crest distance, closed mouth breadth, open mouth breadth, and nose-lip distance) were made by two calibrated examiners and an average was recorded. Because there were no statistically significant differences among races or genders the data were combined. The normative data for seven age groups (6 weeks to 36 months) and five oral-facial parameters are presented.

Imaging evaluation of artificial nipples during bottle feeding.

OBJECTIVES: To determine whether real-time ultrasonography can be used to directly visualize artificial nipples in vivo while an infant is sucking, to compare deformation differences of the artificial nipple with the human nipple during sucking, and to compare the suck mechanism used by the infant with four types of artificial nipples. DESIGN: Nonrandomized clinical study with a control group. SETTING: University-affiliated teaching hospital in Iowa City, Iowa. PARTICIPANTS: A volunteer sample of 35 healthy infants 6 to 12 weeks of age. INTERVENTION: None. MEASUREMENTS/MAIN RESULTS: Images produced by real-time ultrasound of infants during sucking using artificial nipples were measured to determine the percentage lengthening, the percentage lateral compression, and the percentage flattening of nipples. These results were compared with data obtained from studies using breast-fed infants. None of the artificial nipples lengthened like the human nipple. One artificial nipple was significantly more compressible than the human nipple and the remaining three artificial nipples. CONCLUSION: Real-time ultrasonography can be used to visualize artificial nipples in vivo during sucking.

Rumination and vomiting in Prader-Willi syndrome.

Inability to vomit has been cited as characteristic of Prader-Willi syndrome (PWS). Although post-prandial vomiting after gastric by-pass surgery has been reported, neither vomiting under "typical" circumstances or rumination have been described. Prompted by the discovery of several cases of vomiting and rumination, a questionnaire was sent to members of the PWS Association. Approximately 36% (113/313) of affected individuals reportedly experienced at least one episode of vomiting. Induced vomiting was unsuccessful in 9 of 14 cases in whom results were known. However, no complications of Ipecac were reported. We suggest that there is an alteration in the physiologic set-point at which vomiting occurs, leading to a decreased propensity to vomit. Liberal and strict definitions of rumination yielded 15.7% and 10.2% positive responses, respectively. Rumination was associated with a history of vomiting. Enamel deterioration consistent with rumination has been observed, and such changes should be looked for in all PWS children. In several instances, rumination was found to decrease when very strict weight control was lessened. Certain individuals may ruminate under too strict a weight control program, and weight control goals should be evaluated to achieve a reasonable compromise between ideal weight and obesity. Vomiting and rumination do not rule out the diagnosis of PWS.

An unusual triad: microdontia, taurodontia, and dens invaginatus.

A 12 1/2-year-old white boy was examined and found to have permanent teeth that were smaller than those of the average adult. The microdontia was accompanied by taurodontia of the mandibular molars and several teeth with dens invaginatus. The patient was normal in appearance and had no other illness. The pedigree was compatible with X-linked recessive inheritance.