Highly effective cystic fibrosis transmembrane conductance (regulator) modulator therapy: shifting the curve for most while leaving some further behind.

PURPOSE OF REVIEW: Traditional cystic fibrosis (CF) care had been focused on early intervention and symptom mitigation. With the advent of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy (HEMT), in particular, the approval of elexacaftor/tezacaftor/ivacaftor in 2019, there has been a dramatic improvement in outcomes in CF. The purpose of this article is to review the benefits, limitations, and impact of HEMT as well as discuss the new implications, challenges, and hope that modulators bring to people with CF (pwCF). RECENT FINDINGS: HEMT has demonstrated sustained improvement in lung function, nutrition, quality of life, and survival for over 90% of pwCF. As HEMT has delivered such promise, there is a small but significant portion of pwCF who do not benefit from HEMT due to ineligible mutations, intolerance, or lack of accessibility to modulators. SUMMARY: HEMT has significantly improved outcomes, but continued research is needed to understand the new challenges and implications the era of HEMT will bring, as well as how to provide equitable care to those who are unable to benefit from HEMT.

Evaluating dose-limiting toxicities of MDM2 inhibitors in patients with solid organ and hematologic malignancies: A systematic review of the literature.

INTRODUCTION: Mouse double minute 2 protein (MDM2), a negative regulator of the p53 tumour suppressor gene, is frequently amplified in malignancies. MDM2 antagonists have shown efficacy in treating malignancies with MDM2 overexpression and can overcome chemoresistance in acute myeloid leukemia. We systematically evaluated the safety profile of MDM2 inhibitors in the treatment of solid organ and hematologic malignancies. MATERIALS AND METHODS: We searched Medline and EMBASE from January 1947 to November 2018 for prospective clinical studies, in English or French, investigating any MDM2 inhibitor in pediatric or adult cancers, and reporting dose and toxicity outcomes. Primary outcome was dose-limiting toxicity (DLT) and secondary outcome was death. RESULTS: The search yielded 493 non-duplicate citations. Eighteen studies of 10 inhibitors met inclusion criteria (total N = 1005 patients). Two-thirds of included studies did not define DLTs and the reporting of toxicities was highly variable. The most commonly reported DLTs were cytopenias, gastrointestinal toxicity, metabolic disturbances, fatigue and cardiovascular toxicity; there was one death attributed to treatment toxicity. CONCLUSION: MDM2 antagonists have been studied in a variety of malignancies with toxicities similar to other commonly used chemotherapy agents and may represent a safe adjuvant treatment for further study in in acute leukemia.

Engineering of hyaline cartilage with a calcified zone using bone marrow stromal cells.

OBJECTIVE: In healthy joints, a zone of calcified cartilage (ZCC) provides the mechanical integration between articular cartilage and subchondral bone. Recapitulation of this architectural feature should serve to resist the constant shear force from the movement of the joint and prevent the delamination of tissue-engineered cartilage. Previous approaches to create the ZCC at the cartilage-substrate interface have relied on strategic use of exogenous scaffolds and adhesives, which are susceptible to failure by degradation and wear. In contrast, we report a successful scaffold-free engineering of ZCC to integrate tissue-engineered cartilage and a porous biodegradable bone substitute, using sheep bone marrow stromal cells (BMSCs) as the cell source for both cartilaginous zones. DESIGN: BMSCs were predifferentiated to chondrocytes, harvested and then grown on a porous calcium polyphosphate substrate in the presence of triiodothyronine (T3). T3 was withdrawn, and additional predifferentiated chondrocytes were placed on top of the construct and grown for 21 days. RESULTS: This protocol yielded two distinct zones: hyaline cartilage that accumulated proteoglycans and collagen type II, and calcified cartilage adjacent to the substrate that additionally accumulated mineral and collagen type X. Constructs with the calcified interface had comparable compressive strength to native sheep osteochondral tissue and higher interfacial shear strength compared to control without a calcified zone. CONCLUSION: This protocol improves on the existing scaffold-free approaches to cartilage tissue engineering by incorporating a calcified zone. Since this protocol employs no xenogeneic material, it will be appropriate for use in preclinical large-animal studies.

Stress reactivity of emotional and verbal speech content in schizophrenia.

Speech fundamental frequencies (SFFs) are nonverbal sound frequencies that convey emotion in speech. The degree of SFF long-term averaged spectra (LTAS) convergence between conversants reflects aspects of conversant-reported quality of the interaction (e.g., emotional synchrony). This study investigated whether SFF LTAS convergence between inpatients diagnosed with schizophrenia (n = 20) and an interviewer was associated with severity of illness (SOI), formal speech disturbance (FSD), and stress reactivity of FSD. Participants provided speech samples describing stressful and nonstressful life experiences. In the stress condition, SFF LTAS was negatively correlated with SOI and FSD. Moreover, patients exhibiting stress reactivity of FSD also evidenced stress reactivity of SFF LTAS. These findings suggest that the emotional and verbal contents of speech are disrupted by stress in schizophrenia, and SOI is associated with FSD and reduced emotional communication during stressful conditions. The interaction between stress reactivity of FSD and SFF LTAS supports the construct validity of a reactivity dimension in schizophrenia.

Critical components of the pluripotency network are targets for the p300/CBP interacting protein (p/CIP) in embryonic stem cells.

p/CIP, also known as steroid receptor coactivator 3 (SRC-3)/Nuclear Receptor Coactivator 3 (NCoA3), is a transcriptional coactivator that binds liganded nuclear hormone receptors, as well as other transcription factors, and facilitates transcription through direct recruitment of accessory factors. We have found that p/CIP is highly expressed in undifferentiated mouse embryonic stem cells (mESCs) and is downregulated during differentiation. siRNA-mediated knockdown of p/CIP decreased transcript levels of Nanog, but not Oct4 or Sox2. Microarray expression analysis showed that Klf4, Tbx3, and Dax-1 are significantly downregulated in mESCs when p/CIP is knocked down. Subsequent chromatin immunoprecipitation (ChIP) analysis demonstrated that Tbx3, Klf4, and Dax-1 are direct transcriptional targets of p/CIP. Using the piggyBac transposition system, a mouse ESC line that expresses Flag-p/CIP in a doxycycline-dependent manner was generated. p/CIP overexpression increased the level of target genes and promoted the formation of undifferentiated colonies. Collectively, these results indicate that p/CIP contributes to the maintenance of ESC pluripotency through direct regulation of essential pluripotency genes. To better understand the mechanism by which p/CIP functions in ESC pluripotency, we integrated our ChIP and transcriptome data with published protein-protein interaction and promoter occupancy data to draft a p/CIP gene regulatory network. The p/CIP gene regulatory network identifies various feed-forward modules including one in which p/CIP activates members of the extended pluripotency network, demonstrating that p/CIP is a component of this extended network.

Effects of dichotically enhanced electronic communication on crash risk and performance during simulated driving.

In a driving simulator experiment, male and female college students received turn-by-turn driving directions and cognitive tasks while interacting with an experimenter via an audio communication system. In an Enhanced condition (n = 29), lower speech frequencies (containing the speech fundamental frequency) were routed to participants' left ears (with right cerebral-hemisphere processing) and verbal frequencies above the speech fundamental frequency were routed to right ears (with left hemisphere processing). A control group (n = 31) heard unfiltered communications in both ears. Compared to those in the Control condition, participants in the Enhanced condition were significantly less likely to crash and had nonsignificantly lower rates of driving errors (speed infractions, improper lane position, and following distance errors). The results suggest a means of alleviating cognitive load pressure and mitigating crash risk when complex equipment is operated concurrently with two-way electronic communications (cell phone communication while driving, air-to-air and air-to-ground communications, etc.).

Targeted high and low speech frequency bands to right and left ears respectively improve task performance and perceived sociability in dyadic conversations.

Past research shows that the lower nonverbal frequencies of the human voice, beneath .5 kHz, transmit an acoustic signal promoting social convergence and status accommodation between human interlocutors. We conducted a laboratory experiment and a validation study to explore the possible communications benefits of targeting the low-frequency band to the left ears of human participants and the high-frequency band to the right ears. We compare this "Enhanced" condition with two other conditions: a "Confounded" condition, in which the low-frequency band was targeted to participants' right ears and the higher-frequency band to their left ears; and a Control condition, in which the entire unaltered frequency band was targeted to both ears. For the duration of their interaction, experiment participants engaged in dyadic conversations while attempting to complete a task via an audio-visual communication system. Our results show that both the speed and accuracy of task completion were significantly improved in the Enhanced condition. In the second validation study, groups of participants rated the quality of videotaped conversations from the experiment using a semantic differential instrument. The Enhanced condition conversations were rated significantly more affectively favourable than either the unaltered Control or Confounded condition conversations. Overall, our results exhibit potential for enhancing two-way electronic communications and improving task performances in media environments.

Further analysis of a doctor-patient nonverbal communication instrument.

This study examines the reliability and validity of the relational communication scale for observational measurement (RCS-O) using a random sample of 80 videotaped interactions of medical students interviewing standardized patients (SPs). The RCS-O is a 34-item instrument designed to measure the nonverbal communication of physicians interacting with patients. The instrument was applied and examined in two different interview scenarios. In the first scenario (year 1), the medical student's interview objective is to demonstrate patient-centered interviewing skills as the SP presents with a psychosocial concern. In the second scenario (year 3), the student's interview objective is to demonstrate both doctor-centered and patient-centered skills as the SP presents with a case common in primary care. In the year 1 scenario, 19 of the 34 RCS-O items met acceptable levels of inter-rater agreement and reliability. In the year 3 scenario, 26 items met acceptable levels of inter-rater agreement and reliability. Factor analysis indicated that in both scenarios each of the four primary relational communication dimensions was salient: intimacy, composure, formality, and dominance. Measures of correlation and differences involving the RCS-O dimensions and structural features of the interviews (e.g., number of questions asked by the medical student) are examined.

Gene-trap mutagenesis: past, present and beyond.

Although at least 35,000 human genes have been sequenced and mapped, adequate expression or functional information is available for only approximately 15% of them. Gene-trap mutagenesis is a technique that randomly generates loss-of-function mutations and reports the expression of many mouse genes. At present, several large-scale, gene-trap screens are being carried out with various new vectors, which aim to generate a public resource of mutagenized embryonic stem (ES) cells. This resource now includes more than 8,000 mutagenized ES-cell lines, which are freely available, making it an appropriate time to evaluate the recent advances in this area of genomic technology and the technical hurdles it has yet to overcome.

Usefulness of the Framingham risk score and body mass index to predict early coronary artery calcium in young adults (Muscatine Study).

The value of a coronary artery disease prediction algorithm, the Framingham risk score (score), for detecting coronary artery calcium (CAC) was examined in 385 men and 472 women, aged 29 to 43 years. Scores were compared in subjects with and without CAC and were also used to predict presence of CAC. Receiver-operating characteristic curves were computed to compare different prediction models. The score model was compared with age only, natural logarithm of body mass index (lnBMI) only, and score plus lnBMI models. CAC was detected in 30% of men and 16% of women. The mean score was significantly higher in men and women with CAC. For every 2-point increase in the score, the odds of CAC increased by 30% in women and 20% in men. Significant associations between CAC status and risk factors were observed for age in women, and high- density lipoprotein cholesterol and blood pressure in men and women. The area under the receiver-operating characteristic curve for the score was 0.67 and 0.57 for women and men, respectively. When lnBMI was added to the score model, the area increased to 0.76 in women (lnBMI p <0.0001, score p <0.005). For men, the area increased from 0.57 to 0.67, and the score was no longer significant (p >0.60) in the model with lnBMI (p <0.0001). Score predicts CAC in asymptomatic young adults. Inclusion of lnBMI in the score model adds significantly to the prediction of CAC in women and men. The lnBMI model has a greater predictive value than the score in this young population.

Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death.

Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis and tissue homeostasis. In mammals, release of mitochondrial cytochrome c leads to the cytosolic assembly of the apoptosome-a caspase activation complex involving Apaf1 and caspase-9 that induces hallmarks of apoptosis. There are, however, mitochondrially regulated cell death pathways that are independent of Apaf1/caspase-9. We have previously cloned a molecule associated with programmed cell death called apoptosis-inducing factor (AIF). Like cytochrome c, AIF is localized to mitochondria and released in response to death stimuli. Here we show that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation. Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies-the very first wave of cell death indispensable for mouse morphogenesis. AIF-dependent cell death displays structural features of apoptosis, and can be genetically uncoupled from Apaf1 and caspase-9 expression. Our data provide genetic evidence for a caspase-independent pathway of programmed cell death that controls early morphogenesis.

Imaging of coronary calcium: a case for electron beam computed tomography.

Coronary arterial calcification has unequivocally been shown to be a marker of atherosclerosis. To date, much research interest has been generated regarding the quantification of coronary calcification by electron beam computed tomography, and how best to use such measurements to identify and predict those at greatest risk for an adverse cardiac event. This article represents an attempt to provide an objective review of the literature regarding the potential role electron beam computed tomography (EBCT) has as an accurate and cost effective screening modality for coronary arterial disease, as well as a predictor for coronary heart disease.

Alternates to EBCT for coronary calcium.

HCT and EBT imaging of soft plaque and the use of these modalities in CT angiographic applications are important in the non-calcified plaque assessment of coronary artery disease and in the follow-up of treatment.