Expanding small-molecule target space to mRNA translation regulation.

Multiple layers of regulation are in place on mRNA translation to ensure that cells respond in a fast manner to environmental cues in a tissue-specific and mRNA-selective manner. Here, we discuss mRNA translation regulatory mechanisms and potential drug-intervention targets. Taking on a new scientific rational of translation regulation and consequently a new target space, we have developed a unique discovery platform that is able to identify selective small molecule drugs that affect translation of specific proteins. This approach has enabled targeting of proteins that have been considered undruggable. Our discovery platform was repeatedly utilized to identify compounds in multiple therapeutic programs, including fibrosis, oncology, anti-virals and Huntington's disease. In fibrosis, the lead compound ANI-21 has demonstrated a tissue-specific effect in lowering the translation of Collagen-I and superior efficacy over best standard of care, in both cell and animal models, mediated by a novel mechanism of action. This program is expected to enter clinical studies within 12-18 months.

Pneumopericardium, pneumomediastinum and air travel: A case report in a patient with Gardner syndrome.

Onboard aircraft medical emergencies are on the rise as commercial air traffic is increasing. However, thoracic injury secondary to air travel is extremely rare and, most reported injuries are cases of pneumothoraces. Spontaneous pneumomediastinum and pneumopericardium have been barely reported in the medical literature as a complication of air travel. We are reporting a case of spontaneous pneumopericardium and pneumomediastinum in a patient with Gardner's Syndrome after a flight from Central America to New York City. The patient presented with chest discomfort. He was managed conservatively with oxygen therapy as he was hemodynamically stable throughout his stay in the hospital. A thorough work up in hospital including and esophagogram and a CT scan of the chest were none revealing of the cause. However, the patient was noted to have metastatic rectal cancer with lung involvement. The patient was discharged with instructions to avoid air travel.

A Case of Laryngeal Tuberculosis, Endobronchial Tuberculosis and Pulmonary Tuberculosis Coexistent in an Immunocompetent Host.

Historically associated with poor prognosis seen in advanced disease, laryngeal tuberculosis (LTB) now represents only 1% of all cases of tuberculosis (TB). The incidence of LTB has decreased drastically with the introduction of anti-tubercular drugs. LTB can be primary or secondary to pulmonary tuberculosis. LTB can mimic laryngeal cancer. We present a case of primary laryngeal TB with descending tracheobronchial spread in an immunocompetent 71-year-old female who developed progressive dysphonia over several months with unintentional weight loss and non-productive cough. Non-contrast enhanced computed tomography (CT) revealed clustering of subcentimeter stellate nodules in the right upper lung field with an enlarging ground-glass opacity in the right lower lung but did not show structural abnormalities within the neck. Positron emission tomography (PET) showed pathologic fluorodeoxyglucose (FDG) uptake within the larynx and trachea with extension into the left mainstream bronchus as well as the proximal left upper and lower lobe bronchi. Diffuse standardized uptake value (SUV) was greatest in the larynx (20.5). Polymerase chain reaction (PCR) on bronchoscope sputum specimen confirmed Mycobacterium tuberculosis. Findings were consistent with primary laryngeal TB with endobronchial extension. She was started on a four-drug regimen comprising of isoniazid, rifampin, ethambutol, and pyrazinamide with a good response. Her close contacts were treated as well. This case highlights the unusual spread of primary laryngeal TB in an immunocompetent host. Early diagnosis can limit adverse complications and unnecessary exposure to healthcare workers. To our knowledge, this is the first case of primary LTB with proximal spread to the tracheobronchial and pulmonary tuberculosis.

Outbreak of Electronic-Cigarette-Associated Acute Lipoid Pneumonia - North Carolina, July-August 2019.

On September 6, 2019, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr). Electronic cigarettes (e-cigarettes) produce an aerosol by heating a liquid that usually contains nicotine, flavorings, and other chemicals that users inhale, a behavior commonly referred to as "vaping." E-cigarettes can also be used to deliver marijuana and other drugs. In recent months, more than 200 possible cases of acute lung injury potentially associated with vaping were reported from 25 states (1). During July and August 2019, five patients were identified at two hospitals in North Carolina with acute lung injury potentially associated with e-cigarette use. Patients were adults aged 18-35 years and all experienced several days of worsening dyspnea, nausea, vomiting, abdominal discomfort and fever. All patients demonstrated tachypnea with increased work of breathing on examination, hypoxemia (pulse oximetry <90% on room air), and bilateral lung infiltrates on chest x-ray. All five patients shared a history of recent use of marijuana oils or concentrates in e-cigarettes. All of the products used were electronic vaping pens/e-cigarettes that had refillable chambers or interchangeable cartridges with tetrahydrocannabinol (THC) vaping concentrates or oils, which were all purchased on the street. Three of the patients also used nicotine-containing e-cigarettes, and two of the patients smoked marijuana or conventional cigarettes, although none used other illicit drugs. All five patients were hospitalized for hypoxemic respiratory failure; three required intensive care for acute respiratory distress syndrome, one of whom required intubation and mechanical ventilation. All of the patients survived.

Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin-Proteasome Pathway.

The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it. Ubistatin B binds ubiquitin and diubiquitin tighter than a high-affinity ubiquitin receptor and shows strong preference for K48 linkages over K11 and K63. Furthermore, ubistatin B shields ubiquitin conjugates from disassembly by a range of deubiquitinases and by the 26S proteasome. Finally, ubistatin B penetrates cancer cells and alters the cellular ubiquitin landscape. These findings highlight versatile properties of ubistatins and have implications for their future development and use in targeting ubiquitin-signaling pathways.

Left Lung Torsion: Complication of Lobar Resection for an Early Stage Lung Adenocarcinoma.

Lobar torsion is a fatal but fortunately rare occurrence following lung resection. Early clinical signs and radiographic features may be nonspecific resulting in diagnostic delay. A high index of suspicion is vital for early diagnosis and intervention to avoid further parenchymal necrosis and deadly gangrene. We report a case of left lower lobe torsion in a 76-year-old female following elective upper lobectomy for underlying lung adenocarcinoma. Diagnosis was made following highly suggestive radiographic findings prompting bronchoscopy and revision thoracotomy. An emergency detorsion failed to restore lung viability and was followed by completion pneumonectomy. The patient recovered and was discharged on the seventh postoperative day.

Disassembly of Lys11 and mixed linkage polyubiquitin conjugates provides insights into function of proteasomal deubiquitinases Rpn11 and Ubp6.

Protein homeostasis is largely dependent on proteolysis by the ubiquitin-proteasome system. Diverse polyubiquitin modifications are reported to target cellular proteins to the proteasome. At the proteasome, deubiquitination is an essential preprocessing event that contributes to degradation efficiency. We characterized the specificities of two proteasome-associated deubiquitinases (DUBs), Rpn11 and Ubp6, and explored their impact on overall proteasome DUB activity. This was accomplished by constructing a panel of well defined ubiquitin (Ub) conjugates, including homogeneous linkages of varying lengths as well as a heterogeneously modified target. Rpn11 and Ubp6 processed Lys(11) and Lys(63) linkages with comparable efficiencies that increased with chain length. In contrast, processing of Lys(48) linkages by proteasome was inversely correlated to chain length. Fluorescently labeled tetra-Ub chains revealed endo-chain preference for Ubp6 acting on Lys(48) and random action for Rpn11. Proteasomes were more efficient at deconjugating identical substrates than their constituent DUBs by roughly 2 orders of magnitude. Incorporation into proteasomes significantly enhanced enzymatic efficiency of Rpn11, due in part to alleviation of the autoinhibitory role of its C terminus. The broad specificity of Rpn11 could explain how proteasomes were more effective at disassembling a heterogeneously modified conjugate compared with homogeneous Lys(48)-linked chains. The reduced ability to disassemble homogeneous Lys(48)-linked chains longer than 4 Ub units may prolong residency time on the proteasome.

Unique disulfide bonds in epidermal growth factor (EGF) domains of ß3 affect structure and function of αIIbß3 and αvß3 integrins in different manner.

The ß3 subunit of αIIbß3 and αvß3 integrins contains four epidermal growth factor (EGF)-like domains. Each domain harbors four disulfide bonds of which one is unique for integrins. We previously discerned a regulatory role of the EGF-4 Cys-560-Cys-583 unique bond for αIIbß3 activation. In this study we further investigated the role of all four integrin unique bonds in both αIIbß3 and αvß3. We created ß3 mutants harboring serine substitutions of each or both cysteines that disrupt the four unique bonds (Cys-437-Cys-457 in EGF-1, Cys-473-Cys-503 in EGF-2, Cys-523-Cys-544 in EGF-3, and Cys-560-Cys-583 in EGF-4) and transfected them into baby hamster kidney cells together with normal αv or αIIb. Flow cytometry was used to measure surface expression of αIIbß3 and αvß3 and their activity state by soluble fibrinogen binding. Most cysteine substitutions caused similarly reduced surface expression of both receptors. Disrupting all four unique disulfide bonds by single cysteine substitutions resulted in variable constitutive activation of αIIbß3 and αvß3. In contrast, whereas double C437S/C457S and C473S/C503S mutations yielded constitutively active αIIbß3 and αvß3, the C560S/C583S mutation did not, and the C523S/C544S mutation only yielded constitutively active αIIbß3. Activation of C523S/C544S αvß3 mutant by activating antibody and dithiothreitol was also impaired. Molecular dynamics of C523S/C544S ß3 in αIIbß3 but not in αvß3 displayed an altered stable conformation. Our findings indicate that unique disulfide bonds in ß3 differently affect the function of αIIbß3 and αvß3 and suggest a free sulfhydryl-dependent regulatory role for Cys-560-Cys-583 in both αIIbß3 and αvß3 and for Cys-523-Cys-544 only in αvß3.

Intravenous iron therapy and risk for progressive loss of kidney function in patients with chronic kidney disease.

BACKGROUND: Intravenous (IV) iron is used in the treatment of anemia in patients with chronic kidney disease (CKD). Several lines of evidence have brought up potential concerns regarding the effect of IV iron on the kidney, specifically the possibility of IV iron leading to renal injury and hastening the progression of CKD. METHODS: We performed a retrospective analysis of 77 patients to assess the rate of change in kidney function prior to and after IV iron infusion. RESULTS: Patients were followed for an average of 21.3 months (range 2-35) prior and 32.8 months (range 2-58) after the single iron infusion. Sixty-one percent of patients had CKD stage 3 and 30% were at CKD stage IV at the time of iron infusion. Of the 77 patients, 74.1% received iron dextran and 25.9% received ferric gluconate (1 g total). The average slope before and after iron infusion for 1/serum creatinine versus time (months) were -0.0066 and -0.0053, respectively (p = 0.12). The average slope before and after iron infusion for glomerular filtration rate versus time (months) were -0.5439 and -0.2998, respectively (p = 0.14). There was no difference in subgroup analysis in the rate of change in renal function in those with more advanced renal function as opposed to those with more preserved renal function. CONCLUSION: In this limited retrospective study, IV iron dextran or ferric gluconate was not associated with a change in the rate of progression of CKD.