MicroRNA-214 promotes hepatic stellate cell activation and liver fibrosis by suppressing Sufu expression
MicroRNA-214 promotes hepatic stellate cell activation and liver fibrosis by suppressing Sufu expression, Published online: 18 June 2018; doi:10.1038/s41419-018-0752-1
MicroRNA-214 promotes hepatic stellate cell activation and liver fibrosis by suppressing Sufu expressionAnticancer chemotherapy and radiotherapy trigger both non-cell-autonomous and cell-autonomous death
Anticancer chemotherapy and radiotherapy trigger both non-cell-autonomous and cell-autonomous death, Published online: 18 June 2018; doi:10.1038/s41419-018-0747-y
Anticancer chemotherapy and radiotherapy trigger both non-cell-autonomous and cell-autonomous deathDifferential antiviral immunity to Japanese encephalitis virus in developing cortical organoids
Differential antiviral immunity to Japanese encephalitis virus in developing cortical organoids, Published online: 18 June 2018; doi:10.1038/s41419-018-0763-y
Differential antiviral immunity to Japanese encephalitis virus in developing cortical organoidsLong intergenic non-coding RNA 00324 promotes gastric cancer cell proliferation via binding with HuR and stabilizing FAM83B expression
Long intergenic non-coding RNA 00324 promotes gastric cancer cell proliferation via binding with HuR and stabilizing FAM83B expression, Published online: 18 June 2018; doi:10.1038/s41419-018-0758-8
Long intergenic non-coding RNA 00324 promotes gastric cancer cell proliferation via binding with HuR and stabilizing FAM83B expressionMicroRNA-378 is involved in hedgehog-driven epithelial-to-mesenchymal transition in hepatocytes of regenerating liver
MicroRNA-378 is involved in hedgehog-driven epithelial-to-mesenchymal transition in hepatocytes of regenerating liver, Published online: 18 June 2018; doi:10.1038/s41419-018-0762-z
MicroRNA-378 is involved in hedgehog-driven epithelial-to-mesenchymal transition in hepatocytes of regenerating liverClinical trials using agents directed at neuroprotection and remyelination in multiple sclerosis (MS) are needed. As optic neuritis (ON) is common in people with MS and the pathology of ON is similar to other MS lesions in the brain, measurements of the anterior visual system are frequently utilized in neuroprotection and remyelination trials. Understanding the strengths and weaknesses of the measurements is vital when interpreting the results of this research.
Techniques such as visual evoked potentials (VEP) and optical coherence tomography (OCT) are well established in MS and are thought to measure axonal integrity and myelination. Novel imaging techniques can also be used in conjunction with these measurements to provide better insight into optic nerve structure and function. Magnetization transfer imaging (MTR) together with optic nerve area and volume measures neurodegeneration; diffusion tensor imaging (DTI) measures myelination status and neurodegeneration. However, these techniques require various levels of experience to interpret, and all can be confounded by ocular motion and surrounding fat and bone.
This article provides a review of established and novel techniques to measure the anterior visual system in multiple sclerosis with a focus on the evidence to support their use as outcome measures in clinical trials focused on neuroprotection and remyelination therapies.
The high efficiency video coding (HEVC) standard supports a flexible coding tree unit (CTU) partitioning structure, and thus coding efficiency is improved significantly. However, the use of this technique inev...
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Future Oncology, Ahead of Print.
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To stage axillary lymph nodes in women with early-stage breast cancer, sentinel lymph node biopsy (SLNB), rather than axillary lymph node dissection (ALND), has been employed. Moreover, different tracer methods have various advantages and disadvantages. In recent years, carbon nanoparticle suspensions (CNSs) have been used as lymph node tracers during surgeries for thyroid cancer, gastric cancer, and colorectal cancer. The study retrospectively analyzed the feasibility and accuracy of CNS for sentinel lymph node (SLN) mapping in patients with early breast cancer.
This single-center, retrospective study included breast cancer patients who underwent SLNB from January 1, 2016, to December 31, 2017, in the Department of Breast Cancer, Guangdong General Hospital. All patients received standard SLNB surgery using a CNS tracer.
A total of 332 cases were included in this study. The SLN identification rate was 99.1% (329/332), and the mean number of SLNs was 2.6 (range, 1–6). SLN metastasis was found in 62 (18.8%) cases, of which 90.3% were found to be macrometastases. The sensitivity of SLNB was 95.9% (47/49), with a specificity of 100% (42/42), a positive predictive value of 100% (47/47), a negative predictive value of 95.5% (42/44), and a false-negative rate of 4.1% (2/49).
The identification and predictive values of a CNS tracer for SLNB were satisfactory.
Ads and complete payments must be received in writing by the issue's deadline date. These deadlines apply to insertions, cancellations, and changes.
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FLORIDA, Port Charlotte: Stable, 22 year old, progressive independent group seeking residency trained, board certified EM physicians for expansion to second facility. 27k and 22k volume EDs. Full specialty backup. Excellent compensation based on productivity with full time income potential exceeding 350k. Flexible scheduling. Documentation by EMR. Malpractice, Health Insurance, Dental provided. Located on Charlotte Harbor with saltwater access to the Gulf. Short drive to Tampa, Sarasota, Fort Myers, Naples.
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A 9-year-old girl presented to the emergency department with a 1-day history of right hip pain on waking. She denied having any injury, fever, concurrent illnesses, or skin lesions. Her medical history was unremarkable and her immunizations were up to date. On examination, she appeared well, had normal vital signs, and was afebrile. Examination of the right lower extremity did not reveal any edema, erythema, or rashes. She had painful range of motion of the right hip and was unable to weight bear.
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A 15-day-old male infant presented to the emergency department with severe dehydration. He was born at term without complications and had been receiving 3 daily feedings. Physical examination revealed a pulse rate of 80 beats/min, a temperature of 35.5°C (96°F), and absent femoral pulses with poor distal perfusion. Investigations showed a sodium level of 173 mmol/L and platelet level of 60/mm3. Abdominal ultrasonography (Figures 1 to 3) was performed to investigate poor perfusion.
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Integrated, evidence-based trauma care systems reduce injury-related morbidity and mortality while saving costs, both directly in health care dollars and indirectly in societal influence. The American College of Emergency Physicians (ACEP) further supports the following principles related to the advancement of trauma care systems:
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A 19-year-old man with no medical history presented to the emergency department with right upper quadrant abdominal pain 2 hours after being elbowed in the abdomen during a soccer match. Review of systems was pertinent for nausea and vomiting. Pulse rate and blood pressure were within normal limits. Physical examination was notable for right upper quadrant abdominal and right flank tenderness. Laboratory results were notable for a normal CBC count, comprehensive metabolic panel, and urinalysis. The emergency physician performed bedside ultrasonography, which showed hydronephrosis and perinephric fluid (Figures 1 and 2).
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I read with great interest the article by Nishijima et al.1 This was a large, well-designed, prospective study that demonstrated that 3% of adult patients aged 60 years or older who present to the emergency department (ED) with syncope or near syncope may later incur a serious dysrhythmia that may not be apparent during initial ED evaluation. The primary outcome of serious dysrhythmia was appropriately defined according to current American Heart Association guidelines2 and included symptomatic supraventricular tachycardia, the most common primary outcome observed in this study (42 subjects; 40%).
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A 57-year-old man presented to the emergency department with 1 week of left fifth metacarpophalangeal joint swelling and pain that worsened with movement. The patient had tried placing ice on the joint, without relief. He worked as a mechanic in environmental services and thus worked with his hands, but he denied recent direct trauma to the area.
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We appreciate the letter to the editor from Dr. deSouza,1 who astutely points out that certain symptomatic supraventricular tachycardia arrhythmias such as atrioventicular nodal reentrant tachycardia or atrial tachycardia have considerably less morbidity than other supraventricular tachycardia arrhythmias such as atrial fibrillation or atrial flutter in older adults with syncope. We are in agreement that not all supraventricular tachycardia arrhythmias are created equal. This is notable because the majority of serious cardiac arrhythmias identified after emergency department (ED) evaluation in our study were supraventricular tachycardia arrhythmias (42/102; 40%).
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Resident Dr. K scurried through the emergency department from the central pod to a secluded corner that contained a set of built-in wooden shelves, serving as a makeshift filing cabinet, to retrieve the requisite initial orders form (number 2178, version 2.3) to complete the inpatient admission process. Scarcely 10 minutes following submission of the form to the department clerk, the acrimonious beeping of Dr. K's pager startled him as it cut sharply through the raucous din common on a Friday night in the ED.
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Small chest tubes and pigtail catheters are frequently placed at our institution for pleural drainage of pneumothorax and pleural effusions. After placement of a chest tube, secure fixation of the device is paramount to prevent dislodgment and patient discomfort. Traditionally, the chest tube has been anchored with suture, wound around the chest tube in a figure eight fashion, and sutured to the adjacent skin of the patient. This has been the standard of practice for many years. Other methods such as the "Roman sandal"1 or a modified mattress suture2 have been developed and tried, but either with multiple skin punctures or limited success.
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A previously healthy 22-year-old woman presented to the emergency department with worsening abdominal pain and emesis for 3 days. Her vital signs were normal. Physical examination revealed a tender mass suspicious for hepatomegaly, extending from the right upper quadrant to the midabdomen. There was no guarding or rebound tenderness on examination. Laboratory study results were unremarkable and serum pregnancy test was negative. Contrast-enhanced computed tomography (CT) was performed (Figures 1 to 3).
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Sam Quinones's Dreamland: The True Tale of America's Opiate Epidemic is a masterpiece of investigative journalism that is essential reading for any health care provider whose practice has been affected by opioid abuse and who seeks to understand in detail how the country and legions of communities fell victim to the deadly viselike grip of this drug. In ways that echo the strongest points of And the Band Played On: Politics, People, and the AIDS Epidemic, Randy Shilts's 1987 account of the AIDS epidemic, Dreamland serves as a journalistic center of gravity around which the complexities of this current epidemic orbit.
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A 60-year-old man presented to the emergency department with an acute exacerbation of his chronic right groin pain after slipping. He had end-stage renal disease requiring dialysis, cirrhosis, diabetes, and congestive heart failure. His pulse rate and temperature were normal, and his examination result was remarkable for a 10-cm mass in the right hemiscrotum. A CBC count was normal. Scrotal ultrasonography was obtained (Figure 1) and compared with previous computed tomography (CT) performed 6 months previously (Figure 2).
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Jon Kerstetter is an emergency physician. He is also a soldier, a patient, and an author. In his memoir, Crossings, he writes about the intersection of these roles.
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A 68-year-old woman presented to the emergency department with pain, redness, and swelling of the right periorbital region for 5 days (Figure 1). Visual acuity was 20/25 bilaterally, and she had no deficits or pain with extraocular movements and no uptake of fluorescein to the corneas. There was some eyelid sparing. On further discussion, the patient noted that before symptoms onset she was at an outdoor flea market and experienced a "twitching" sensation of her eye. On the advice of a vendor, she rubbed a plant he provided around her eye to alleviate the symptoms (Figure 2).
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As a young black female physician, I have much appreciation for the article "When Race Becomes an Issue in Emergency Department Treatment," published in January's edition of Annals.1 Events and access to platforms in recent years have made it increasingly difficult for issues of race to be ignored. The consideration of these issues in a major publication in our field is crucial.
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The American College of Emergency Physicians (ACEP) recognizes that alcohol misuse and abuse are significant risk factors for preventable diseases, injuries, and premature death. ACEP also acknowledges that print, broadcast, Internet, and social media advertising of alcohol may play a significant role in promoting underage and unhealthy alcohol consumption. Therefore, ACEP strongly opposes the promotion of alcohol that (1) may be perceived as directed toward youth; (2) draws a positive correlation between physical performance and the consumption of alcoholic beverages; and (3) depicts the irresponsible use of alcohol without showing its adverse consequences.
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"I don't want no turkey sandwich. Go back and get me a damn tuna!" My patient rebukes my efforts to care for him on a busy Friday night shift, and throws the plastic-wrapped food to the floor.
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Nestled in the fine print of many emergency physicians' contracts are noncompete clauses, also known as restrictive covenants (RC). These agreements prohibit a physician from working in a defined geographic area for a predetermined period after the conclusion of a contract with an employer.
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The study evaluated the in vitro activity of ceftolozane-tazobactam (C/T) against 94 unique clinical isolates of Enterobacter cloacae complex (ECC). No difference was observed according to the ECC cluster. The in vitro activity greatly varied depending on the β-lactamase-producing profile: 100%, 67% and 19% of wild-type, ESBL-producing, and AmpC-overproducing strains were susceptible to C/T, respectively. The use of C/T could be of interest for the treatment of some infections caused by ESBL-producing AmpC-non-overexpressing ECC isolates.
Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a worse clinical outcome with increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus has a dual mode of action causing inhibition of the peptidoglycan synthesis and membrane depolarization. CF-associated MRSA infections remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for complicated skin infections and hospital-acquired pneumonia, the activity against CF- associated S. aureus infections has not been investigated. In this work, we studied the activity of telavancin against CF S. aureus strains collected from diverse geographical CF centers in the USA. We found that telavancin-MIC90 was 0.06 μg/ml, 8-fold lower than ceftaroline or daptomycin and 25-fold lower than linezolid and vancomycin. We demonstrate that telavancin at serum-free concentrations has rapid bactericidal activity with a decrease of more than 3 log10 CFU/ml during the first 4 to 6 hours of treatment, performing better in this assay than vancomycin and ceftaroline, including S. aureus resistant to ceftaroline.
Telavancin resistance was infrequent (0.3%), although we found that it can occur in- vitro in both CF- and non-CF S. aureus strains by progressive passages with sub-inhibitory concentrations. Genetic analysis of telavancin in-vitro mutants showed gene polymorphisms in cell wall and virulence genes, and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for CF infections with potent in-vitro activity and low resistance potential.
A pan-azole-resistant Aspergillus fumigatus strain with the cyp51A mutations Gly138Ser and Asn248Lys was isolated from a patient receiving long-term voriconazole treatment. PCR fragments containing cyp51A with the mutations were introduced along with Cas9 protein and single-guide RNA into the azole-resistant/susceptible strains. Recombinant strains showed increased susceptibility via the replacement of Ser138 by glycine. Genetic recombination, which has been hampered thus far in clinical isolates, can now be achieved using Cas9/CRISPR genome editing.
Tribendimidine is a broad-spectrum anthelmintic available in China, which is currently being pursued for US Food and Drug Administration approval for soil-transmitted helminth infections. Pharmacokinetic (PK) studies with tribendimidine in children, the main target group for treatment programs, have not been conducted to date. In the framework of a dose-ranging study in hookworm infected school-aged children in Côte d'Ivoire, children were either treated with 100 mg, 200 mg, or 400 mg tribendimidine. Dried blood spot samples were collected up to 22 hours after treatment. The active metabolite, deacetylated amidantel (dADT) and its metabolite acylated dADT (adADT) were quantified using liquid chromatography tandem mass spectrometry. PK parameters were calculated using a noncompartmental model and univariate logistic regression was applied using maximal blood concentrations (Cmax) and area under the blood concentration-time curve (AUC0-22h) as predictors of drug efficacy. Dried blood spot samples of 101 children were analyzed. We observed a less than proportional and proportional exposure in dADT's median Cmax and AUC0-22h, respectively, following administration of 100 mg (Cmax=853 ng/ml; AUC0-22h =3,019 h*ng/ml) and 400 mg (Cmax=2,275ng/ml; AUC0-22h =12,530 h*ng/ml) tribendimidine. There were large, dose-independent variations in the time to Cmax (Tmax) and ratios of dADT to adADT. We did not detect an influence of Cmax or AUC0-22h of dADT or adADT on drug efficacy or adverse events. Since our study population was bearing hookworm infection of mainly low intensity, additional studies in heavy intensity infections might be required to confirm this observation.
Letermovir is a human cytomegalovirus (CMV) terminase inhibitor recently approved as prophylaxis in stem cell transplant recipients. In further studies of emerging drug resistance, a baseline laboratory CMV strain was serially propagated in cell culture under a combination of letermovir and ganciclovir. In 8 experiments, UL56 terminase gene mutations were detected beginning at 10 passages, including novel amino acid substitutions V236A, L328V and A365S, in a region previously associated with letermovir resistance. Outside this region, UL56 substitution C25F was detected at moderate drug concentrations in 2 experiments, as either the first detected mutation, or adding to a preexisting substitution V231L. In all cases, mutation at UL56 codon 325 conferring absolute letermovir resistance eventually developed at a median of 20 passages. No UL97 kinase or UL54 DNA polymerase mutations relevant to ganciclovir resistance were detected until many passages after the first detection of UL56 mutations. UL56 substitutions V236A, L328V and A365S were shown to confer borderline or low-grade letermovir resistance, while C25F conferred 5.4-fold increased letermovir resistance (EC50) by itself and 46-fold in combination with V231L. The evolution of resistance mutations sooner in UL56 than in UL54 or UL97 is consistent with prior in vitro observations, and UL56 codon 25 is a genetic locus for letermovir resistance distinct from those previously described.
Optimal doses for anti-tuberculosis (TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosages ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) for at least 4 weeks had blood samples collected at pre-dose, 1, 2, 4, and 8-hours post-dose. Drug concentrations were determined by validated liquid chromatography mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, and the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by one-compartment model and that for INH and EMB by two-compartment model. Cmax and AUC targets were based on published results in children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except for N-acetyl transferase 2 non-slow (rapid and intermediate) acetylators in the lower weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB.
Fitness costs are key determinants of whether drug resistance alleles establish and how fast they spread within populations. More than 125 different kelch13 alleles, each containing a different amino acid substitution, have arisen in SE Asian malaria parasite (Plasmodium falciparum) populations under artemisinin selection over the past 15 years in a dramatic example of a soft selective event. However, just one of these alleles (C580Y) is now outcompeting other alleles in multiple different countries and is spreading towards fixation. Here we examine the fitness consequences of C580Y, relative to another less successful kelch13 mutation (R561H), to try to explain the distinctive dynamics of C580Y. We hypothesized that C580Y will show lower fitness costs relative to other kelch13 substitutions in the absence of artemisinin treatment. We used CRISPR/Cas9 methods to introduce single mutations (C580Y or R561H), or synonymous control edits into a wildtype parasite isolated on the Thailand-Myanmar border, conducted replicated head-to-head competition assays, and determined the outcome of competition using deep sequencing of kelch13 amplicons. Contrary to our predictions, these experiments reveal that C580Y carries higher fitness costs (s=0.15 ± 0.008 [1 s.e.]) than R561H (s=0.084 ± 0.005). Furthermore, R561H outcompetes C580Y in direct competition (s=0.065 ± 0.004). We conclude that fitness costs of C580Y in isolation are unlikely to explain the rapid spread of this substitution.
We tested the in vitro susceptibility of ceftazidime-avibactam and ceftolozane-tazobactam and 13 other antibiotics against 91 Burkholderia cepacia complex (BCC) strains isolated from cystic fibrosis patients since 2012. Highest susceptibility (82%) was found for trimethoprim-sulfamethoxazole. Respectively, 81% and 63% of all BCC strains were susceptible to ceftazidime-avibactam and ceftolozane-tazobactam. For temocillin, ceftazidime, piperacillin-tazobactam and meropenem, at least 50% of the strains were susceptible. B. stabilis seems to be more resistant than other BCC species.
The aim of the study was to evaluate the antimicrobial susceptibility of 866 Neisseria meningitidis invasive strains during 11-years of surveillance in Italy. Two and six strains were resistant to ciprofloxacin and rifampin, respectively. Forty-five percent were penicillin intermediate (PenI) associated with hypervirulent serogroup C clonal complex 11. All the strains were susceptible to cephalosporins.
Multidrug-resistant Acinetobacter baumannii infection has recently emerged as a worldwide clinical problem and colistin is increasingly being used for last resort therapy. Despite its favorable bacterial killing, resistance and heteroresistance (HR) to colistin have been described. The purpose of the present study is to investigate the role of the PmrAB regulatory pathway in laboratory-selected mutants representative of global epidemic strains. From three unrelated A. baumannii clinical strains (Sequence Type 2, 3 and 20), eight colistin resistant mutants were selected. Half of the mutants showed HR to colistin according to the reference method (Population Analysis Profiling), whereas the other half exhibited stable resistance. M12I mutation within pmrA and M308R, S144KLAGS and P170L mutations for pmrB, were associated with HR to colistin while T235I, A226T and P233S mutations within pmrB were associated with stable resistance. The transcripts levels of the pmrCAB operon were upregulated in all the mutants. Compensatory mutations were explored for some mutants. A single mutant (T235I) displayed a compensatory mutation through ISAba1 mobilization within the pmrB gene that was associated with the loss of colistin resistance. The mutant resistance phenotype associated with T235I was partially restored in a trans-complementation assay turning to HR. The level of colistin resistance is correlated with the level of expression of pmrC in the trans-complemented strains. This report shows the role of different mutations in the PmrAB regulatory pathway and warns on the development of colistin HR that could be present but not easily detected through routine testing.
Data are limited on the frequency of gyrA and gyrB mutations in fluoroquinolone-resistant isolates of the Mycobacterium avium complex (MAC) and M. abscessus complex (MABC). In our analysis, we did not find any resistance-associated mutations in gyrA or gyrB in 105 clinical isolates of MAC or MABC, including 72 moxifloxacin-resistant isolates. Our findings suggest that mechanisms other than gyrA and gyrB mutations contribute to moxifloxacin resistance in these organisms.
Flaviviruses constitute an increasing source of public health concern with growing numbers of pathogens causing disease, and a geographic spread to temperate climates. Despite a large body of evidence supporting mutagenesis as a conceivable antiviral strategy, there is currently no data on the sensitivity to increased mutagenesis for Zika virus (ZIKV) and Usutu virus (USUV), two emerging flaviviral threats. In this study, we demonstrate that both viruses are sensitive to three ribonucleosides that have shown mutagenic activity against other RNA viruses – favipiravir, ribavirin and 5-fluorouracil – while they remain unaffected by a mutagenic deoxyribonucleoside. Serial cell culture passages of ZIKV in the presence of these compounds resulted in the rapid extinction of infectivity, suggesting elevated sensitivity to mutagenesis. USUV extinction was achieved when a 10-fold dilution was applied between every passage, but not in experiments involving undiluted virus, indicating an overall lower susceptibility than ZIKV. Although both viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin) while USUV replication is suppressed more efficiently by 5-fluorouracil. These differences in sensitivity typically correlate with the increases in the mutation frequencies observed in each nucleoside treatment. These results are relevant to the development of efficient therapies based on lethal mutagenesis, and support the rational selection of different mutagenic nucleosides for each pathogen. We will discuss the implications of these results to the fidelity of flavivirus replication, and the design of antiviral therapies based on lethal mutagenesis.
Sequential methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients following attempted mupirocin nasal decolonisation showed an increase in mupirocin resistance (MR) from 6.6% to 20%. MR isolates from patients who failed decolonization yielded indistinguishable spa types and carried multiple antimicrobial- and antiseptic-resistance genes, which may guide infection control and prevention.
Pyrrolocytosines RX-04A-D are designed to bind to the bacterial 50S ribosomal subunit differently from currently-used antibiotics. The four analogs had broad anti-Gram-negative activity: RX-04A inhibited 94.7% of clinical Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa at 0.5-4 μg/ml, with no MICs >8 μg/ml. MICs for multi-resistant carbapenemase producers were up to two-fold higher than for control strains, with values ≥8 μg/ml for one Serratia isolate with porin and efflux lesions. mcr-1 did not affect MICs.
Expression of the quinolone resistance gene qnrS1 is increased by quinolones, but, unlike induction of some other qnr genes, the bacterial SOS system is not involved and no lexA box is found upstream. Nonetheless, at least 205-bp of upstream sequence is required for induction to take place. An upstream sequence bound to beads trapped potential binding proteins from cell extracts that were identified by mass spectrometry as Dps, Fis, Ihf, Lrp, CysB, and YjhU. To further elucidate their role a reporter plasmid linking the qnrS1 upstream sequence to lacZ was introduced into cells of the Keio collection with single gene deletions and screened for lacZ expression. Mutants in ihfA and ihfB had decreased lacZ induction while induction in a cysB mutant was increased and dps, fis, lrp, yjhU and other mutants showed no change. The essential upstream sequence contains potential binding sites for Ihf and DnaA. A dnaA deletion could not be tested because it provides essential functions in cell replication, but increased dnaA expression decreased qnrS1 induction while decreased dnaA expression enhanced it implying a role for DnaA as a repressor. In a mobility shift assay purified IhfA, IhfB, and DnaA proteins (but not CysB) were shown to bind to the upstream segment. Induction decreased in a gyrA quinolone-resistant mutant indicating that GyrA also has a role. Thus, quinolones acting through proteins DnaA, GyrA, IhfA, and IhfB regulates expression of qnrS1.
Microbes encode many uncharacterized gene clusters that may produce antibiotics and other bioactive small molecules. Methods for activating these genes are needed to explore their biosynthetic potential. A transposon containing an inducible promoter was randomly inserted into the genome of the soil bacterium Burkholderia thailandensis in order to induce antibiotic expression. This screen identified the polyketide/non-ribosomal peptide thailandamide as an antibiotic and discovered its regulator, AtsR. Mutants of Salmonella resistant to thailandamide had mutations in the accA gene for acetyl-CoA carboxylase, which is one of the first enzymes in the fatty acid synthesis pathway. A second copy of accA in the thailandamide synthesis gene cluster keeps B. thailandensis resistant to its own antibiotic. These genetic techniques will likely be powerful tools for discovering other unusual antibiotics.
Over the past decade, the prevalence of infections involving Methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics has shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate 200 mg PO or IV once daily for 3 doses, with minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetics was performed using maximum-likelihood, expectation maximization method, and the disposition of TZD was described by a 2-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean (%CV) sputum-to-unbound plasma penetration ratio of 2.88 (50.3). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 L/h, 61.6 ± 6.94 L, and 1.04 ± 0.232 respectively. The total clearance is higher in CF patients when compared with healthy volunteers; however, it is similar to published data in patients with complicated skin and skin structure infections (cSSSI). This study demonstrates the oral bioavailability of tedizolid is excellent in patients with CF, and the plasma pharmacokinetics are similar to that reported for patients with cSSSI.
Trypanosomatid parasites cause diseases in humans and livestock. It was reported that partial inhibition of the vacuolar ATPase (V-ATPase) affects dependence of Trypanosoma brucei on its mitochondrial genome (kDNA), a target of the anti-trypanosomatid drug isometamidium. Here we report that V-ATPase inhibition with bafilomycin A1 (BafA) provides partial resistance to genetic knockdown of mitochondrial gene expression. BafA does not promote long-term survival after kDNA loss, but in its presence, isometamidium causes less damage to kDNA.
Objectives: To investigate the population pharmacokinetics (PK) of amoxicillin in ICU burn patients and the optimal dosage regimens.
Methods: Prospective study involving 21 consecutive burn patients receiving amoxicillin. PK data were analysed using non-linear mixed effects modelling. Monte-Carlo simulations assessed the influence of various amoxicillin dosage regimens with identified covariates on the probability to achieve a target (PTA) value of time during which free amoxicillin concentrations in plasma exceeded the minimal inhibitory concentration (fT>MIC).
Results: A two-compartment model best described the data. Creatinine clearance (CLCR) and body weight (BW) influenced amoxicillin CL and central volume of distribution (V1), respectively. The median CLCR (Cockcroft-Gault formula) was high (128 mL/min) with 25% of patients having CLCR > 150 mL/min. The CL, V1 and t1/2 values at steady-state for a patient with a CLCR of 110 mL/min and BW of 70 kg were 13.6 L/h, 9.7 L and 0.8 h, respectively. Simulations showed that a target fT>MIC ≥ 50% was achieved (PTA > 90%) with standard amoxicillin dosage regimens (1-2 g q6-8 h) when the MIC was low (< 1 mg/L). However, increased dosages of up to 2 g/4 h were necessary in patients with augmented CLR or higher MIC. Prolonging amoxicillin infusion from 30 min to 2 h had a favourable effect on target attainment.
Conclusion: This population analysis shows an increased amoxicillin CL and substantial CL PK variability in burn patients compared to literature data with non-burn patients. Situations of augmented CLCR and/or high bacterial MIC target values may require dosage increases and longer infusion durations.
Scabies is a major and potentially growing public health problem worldwide with an unmet need for acaricidal agents with greater efficacy and improved pharmacological properties for its treatment. The objective of the present study was to assess the efficacy and describe the pharmacokinetics profile of a novel acaricide, afoxolaner (AFX), in a relevant experimental porcine model. Twelve pigs were experimentally infested and treated either with 2.5 mg/kg single dose oral AFX (n = 4), 0.2 mg/kg two-doses 8 days apart oral ivermectin (IVM, n = 4), or no treatment against scabies (n = 4). Response to treatment was assessed by reduction of mite counts in skin scrapings as well as clinical and pruritus scores over time. Plasma and skin pharmacokinetic profiles for both AFX and IVM were evaluated. AFX efficacy was 100% at days 8 and 14 post-treatment and remained unchanged until the study-end (day 45). IVM efficacy was 86% and 97% on days 8 and 14, respectively, with a few mites recovered at study-end. Clinical and pruritus scores decreased in both treated groups and remained constant in the control group. Plasma mean residence times (MRT) were 7.1±2.4 and 1.1±0.2 days for AFX and IVM, respectively. Skin MRT values were 16.2±16.9 and 2.7±0.5 days for AFX and IVM, respectively. Overall, a single oral dose of AFX was efficacious for the treatment of scabies in experimentally infested pigs and showed a remarkably long MRT in plasma and notably in the skin.
MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here we demonstrate that BRAFV600E-mutated colorectal cancers acquire resistance to MEK1 inhibition by inducing expression of the scaffold protein CEMIP through a beta-catenin- and FRA-1-dependent pathway. CEMIP was found in endosomes and bound MEK1 to sustain ERK1/2 activation in MEK1 inhibitor-resistant BRAFV600E-mutated colorectal cancers. The CEMIP-dependent pathway maintained c-Myc protein levels through ERK1/2 and provided metabolic advantage in resistant cells, potentially by sustaining amino acids synthesis. CEMIP silencing circumvented resistance to MEK1 inhibition, partly, through a decrease of both ERK1/2 signaling and c-Myc. Together, our data identify a cross-talk between Wnt and MAPK signaling cascades, which involves CEMIP. Activation of this pathway promotes survival by potentially regulating levels of specific amino acids via a Myc-associated cascade. Targeting this node may provide a promising avenue for treatment of colon cancers that have acquired resistance to targeted therapies.
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To clarify the significance of circulating tumor cells (CTC) undergoing epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) patients, we used an advanced CanPatrol™ CTC-enrichment technique and in situ hybridization (ISH) to enrich and classify CTC from blood samples. 101 of 112 (90.18%) HCC patients were CTC-positive, even with early-stage disease. CTC were also detected in 2 of 12 hepatitis B virus (HBV) patients, both of whom had small HCC tumors detected within 5 months. CTC count ≥16 and mesenchymal-CTC (M-CTC) percentage ≥2% prior to resection were significantly associated with early recurrence, multi-intrahepatic recurrence, and lung metastasis. Postoperative CTC monitoring in 10 patients found that most had an increased CTC count and M-CTC percentage before clinically detectable recurrence nodules appeared. Analysis of HCC with high CTC count and high M-CTC percentage identified 67 differentially expressed cancer-related genes involved in cancer-related biological pathways (e.g. cell adhesion and migration, tumor angiogenesis, and apoptosis). One of the identified genes, BCAT1, was significantly upregulated, and knockdown in Hepg2, Hep3B, and Huh7 cells reduced cell proliferation, migration, and invasion while promoting apoptosis. A concomitant increase in epithelial marker expression (EpCAM and E-cadherin) and reduced mesenchymal marker expression (vimentin and Twist) suggests that BCAT1 may trigger the EMT process. Overall, CTC were highly correlated with HCC characteristics, representing a novel marker for early diagnosis and a prognostic factor for early recurrence. BCAT1 overexpression may induce CTC release by triggering EMT and may be an important biomarker of HCC metastasis.
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Purpose: Zinc metallochaperones (ZMCs) are a new class of anti-cancer drugs that reactivate zinc deficient mutant p53 by raising and buffering intracellular zinc levels sufficiently to restore zinc binding. In vitro pharmacodynamics of ZMCs indicate that p53 mutant activity is ON by 4-6 hours and is OFF by 24. We sought to understand the mechanism of this regulation and to translate these findings pre-clinically. We further sought to innovate the formulation of ZMCs to improve efficacy. Experimental Design: We performed in vitro mechanistic studies to determine the role of cellular zinc homeostatic mechanisms in the transient pharmacodynamics of ZMCs. We conducted pre-clinical pharmacokinetic (PK), pharmacodymanic (PD) and efficacy studies using a genetically engineered murine pancreatic cancer model (KPC) to translate these mechanistic findings and investigate a novel ZMC formulation. Results: In vitro, cellular zinc homeostatic mechanisms that restore zinc to its physiologic levels function as the OFF switch in ZMC pharmacodynamics. In vivo PK studies indicate that ZMCs have a short half life (<30 minutes), which is sufficient to significantly improve survival in mice expressing a zinc deficient allele (p53R172H) while having no effect in mice expressing a non-zinc deficient allele (p53R270H). We synthesized a novel formulation of the drug in complex with zinc and demonstrate this significantly improves survival over ZMC1. Conclusions: Cellular zinc homeostatic mechanisms function as an OFF switch in ZMC pharmacodynamics indicating that a brief period of p53 mutant reactivation is sufficient for on-target efficacy. ZMCs synthesized in complex with zinc are an improved formulation.
Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of pathologically expanded myeloid cells with immunosuppressive activity. In human disease three major MDSC subpopulations can be defined as monocytic M-MDSC, granulocytic PMN-MDSC and early stage e-MDSC, which lack myeloid lineage markers of the former two subsets. It was the purpose of this study to determine and compare the immunosuppressive capacity and clinical relevance of each of these subsets in patients with solid cancer. Experimental Design: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in a cohort of 49 patients with advanced head and neck cancer (HNC) and 22 patients with urological cancers. Sorted and purified MDSC subsets were tested in vitro for their T cell suppressive capacity. Frequency of circulating MDSC was correlated with overall survival of HNC patients. Results: A high frequency of PMN-MDSC most strongly correlated with poor overall survival in HNC. T cell suppressive activity was higher in PMN-MDSC compared with M-MDSC and e-MDSC. A subset of CD66b+/CD11b+/CD16+ mature PMN-MDSC displayed high expression and activity of arginase I, and was superior to the other subsets in suppressing proliferation and cytokine production of T cells in both cancer types. High levels of this CD11b+/CD16+ PMN-MDSC, but not other PMN-MDSC subsets, strongly correlated with adverse outcome in HNC. Conclusions: A subset of mature CD11b+/CD16+ PMN-MDSC was identified as the MDSC subset with the strongest immunosuppressive activity and the highest clinical relevance.
Purpose: To develop a radiomics signature based on preoperative magnetic resonance imaging (MRI) to estimate disease-free survival (DFS) in patients with invasive breast cancer and to establish a radiomics nomogram that incorporates the radiomics signature and MRI and clinicopathological findings. Experimental Design: We identified 294 patients with invasive breast cancer who underwent preoperative MRI. Patients were randomly divided into training (n = 194) and validation (n = 100) sets. A radiomics signature (Rad-score) was generated using an elastic net in the training set, and the cutoff point of the radiomics signature to divide the patients into high- and low-risk groups was determined using receiver operating characteristic curve analysis. Univariate and multivariate Cox proportional hazards model and Kaplan-Meier analysis were used to determine the association of the radiomics signature, MRI findings, and clinicopathological variables with DFS. A radiomics nomogram combining the Rad-score and MRI and clinicopathological findings was constructed to validate the radiomic signatures for individualized DFS estimation. Results: Higher Rad-scores were significantly associated with worse DFS in both the training and validation sets (P = 0.002 and 0.036, respectively). The radiomics nomogram estimated DFS (C-index, 0.76; 95% confidence interval [CI], 0.74-0.77) better than the clinicopathological (C-index, 0.72; 95% CI, 0.70-0.74) or Rad-score-only nomograms (C-index, 0.67; 95% CI, 0.65-0.69). Conclusions: The radiomics signature is an independent biomarker for the estimation of DFS in patients with invasive breast cancer. Combining the radiomics nomogram improved individualized DFS estimation.
Purpose: Long non-coding RNAs (lncRNAs) play key roles in human cancers. Here, FEZF1-AS1, a highly overexpressed lncRNA in colorectal cancer (CRC), was identified by lncRNA microarrays. We aimed to explore the roles and possible molecular mechanisms of FEZF1-AS1 in CRC. Experimental Design: LncRNA expression in CRC tissues was measured by lncRNA microarray and qRT-PCR. The functional roles of FEZF1-AS1 in CRC were demonstrated by a series of in vitro and in vivo experiments. RNA pull-down, RNA immunoprecipitation and luciferase analyses were used to demonstrate the potential mechanisms of FEZF1-AS1. Results: We identified a series of differentially expressed lncRNAs in CRC using lncRNA microarrays, and revealed that FEZF1-AS1 is one of the most overexpressed. Further validation in two expanded CRC cohorts confirmed the upregulation of FEZF1-AS1 in CRC, and revealed that increased FEZF1-AS1 expression is associated with poor survival. Functional assays revealed that FEZF1-AS1 promotes CRC cell proliferation and metastasis. Mechanistically, FEZF1-AS1 could bind and increase the stability of the pyruvate kinase 2 (PKM2) protein, resulting in increased cytoplasmic and nuclear PKM2 levels. Increased cytoplasmic PKM2 promoted pyruvate kinase activity and lactate production (aerobic glycolysis), whereas FEZF1-AS1-induced nuclear PKM2 upregulation further activated STAT3 signaling. In addition, PKM2 was upregulated in CRC tissues and correlated with FEZF1-AS1 expression and patient survival. Conclusions: Together, these data provide mechanistic insights into the regulation of FEZF1-AS1 on both STAT3 signaling and glycolysis by binding PKM2 and increasing its stability.
Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease
Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease, Published online: 19 June 2018; doi:10.1038/s41416-018-0141-7
Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease
MONDAY, June 18, 2018 -- Single-sample confirmatory testing for diabetes has a high positive predictive value for subsequent diagnosis, according to a study published online June 19 in the Annals of Internal Medicine. Elizabeth Selvin, Ph.D.,...
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MONDAY, June 18, 2018 -- Pharmacists can help increase adult vaccination rates by offering vaccination at lower cost and greater convenience, according to a study published by the Pacific Research Institute. In a study entitled "Promoting Access and...
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MONDAY, June 18, 2018 -- Approximately one-third of U.S. children and adolescents use dietary supplements, according to a research letter published online June 18 in JAMA Pediatrics. Dima M. Qato, Pharm.D., Ph.D., from University of Illinois at...
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MONDAY, June 18, 2018 -- The American Medical Association (AMA) recently adopted a policy aimed at improving physician access to mental health care in response to physician depression, burnout, and suicide. The policy aims to further reduce stigma...
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MONDAY, June 18, 2018 -- Use of medications for opioid use disorder (MOUD) is associated with a reduction in all-cause and opioid-related mortality after opioid overdose, according to a study published online June 19 in the Annals of Internal...
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Spinal fracture rates from NAT have been reported in
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AJP Rep 2018; 08: e134-e137
DOI: 10.1055/s-0038-1645878
Healthy looking newborns may have severe combined immunodeficiency (SCID), and neonatologists frequently are the first physicians to encounter these patients. Physicians usually have a high index of suspicion for this condition in presence of certain risk factors (unexplained infants' deaths, consanguinity); however, >80% of infants with SCID have no positive family history. A timely diagnosis of this condition is crucial in decreasing both mortality and morbidity. The only way to detect SCID prior to the onset of infections is newborn screening (NBS). In term infants, NBS has 99.99% sensitivity for SCID, with no false negatives. In preterm infants, screening is less accurate due to a lack of standard T cell receptor excision circle (TREC) values in this age group. We report a case of SCID in term infants born to consanguineous parents who were presented with clinical and laboratory findings of erythroderma, severe infection, failure to thrive, eosinophilia, and elevated immunoglobulin E (IgE) together with immunodeficiency. A timely diagnosis was followed by successful hematopoietic stem cell transplantation (HSCT) therapy.
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Table of contents | Abstract | open access Full text
Fractionated total body-irradiation (FTBI) delivering 12Gy in 6 fractions is considered as the standard schedule prior to transplant. For radiotherapy department organization, twice-daily FTBI schedule is a highly time-consuming and agenda disrupting technique. One option to increase TBI offer is to use only one fraction/day. Our report demonstrate that 12Gy-FTBI can be delivered safely in terms of disease control and survival following a single dose of 3 or 4Gy per day. This is of considerable practical importance for radiotherapy centers organization. Further analyses regarding non-lethal acute and late toxicities are planned.
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This study investigated the efficacy of combination therapy with intravenously injected microglia and radiotherapy in a preclinical model of spontaneous malignant glioma. The combination therapy increased infiltrated microglia and CD8-positive T cells and prolonged the survival of transgenic rats spontaneously developing malignant glioma. Combined immunocellular therapy and radiotherapy may provide a novel treatment strategy for malignant glioma.
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In this position paper, the American College of Physicians (ACP) examines the challenges women face in the U.S. health care system across their lifespans, including access to care; sex- and gender-specific health issues; variation in health outcomes compared with men; underrepresentation in research studies; and public policies that affect women, their families, and society. ACP puts forward several recommendations focused on policies that will improve the health outcomes of women and ensure a health care system that supports the needs of women and their families over the course of their lifespans.
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Radiofrequency ablation (RFA) is safe and effective for eradicating Barrett's esophagus (BE), but associated with significant postprocedural pain. Alternatively, balloon-based focal cryoablation (CRYO) has recently been developed, which preserves the extracellular matrix and might therefore be less painful. Although data for CRYO are still limited, uncontrolled studies suggest comparable safety and efficacy to RFA in eradicating limited BE areas. Therefore, secondary endpoints such as pain might become decisive for treatment selection.
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Over the past decade, endoscopic ultrasound-guided biliary drainage (EUS-BD) has emerged as an effective alternative biliary drainage method after unsuccessful ERCP.
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Zyflamend, a blend of herbal extracts, effectively inhibits tumor growth using preclinical models of castrate-resistant prostate cancer mediated in part by 5′-adenosine monophosphate-activated protein kinase (...
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As the patents on some widely used drugs to treat cancer expire in the coming years, biosimilar drugs are being developed for the treatment of patients with cancer. Are biosimilars effective and will they expand treatment options for patients?
MONDAY, June 18, 2018 -- For overweight and obese older adults with knee osteoarthritis (OA), greater weight loss is associated with superior clinical and mechanistic outcomes, according to a study published online June 18 in Arthritis Care &...
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MONDAY, June 18, 2018 -- Intensive care unit (ICU) telemedicine is associated with a reduction in ICU patient interhospital transfers, according to a study published online June 15 in CHEST. Spyridon Fortis, M.D., from the Iowa City Veterans Affairs...
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MONDAY, June 18, 2018 -- Individuals at high cardiovascular risk who are assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts have reduced incidence of major cardiovascular events compared with those assigned to a...
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MONDAY, June 18, 2018 -- Preterm birth and/or low-birth weight (PT/LBW) infants have decreased educational qualifications and rates of employment in adulthood, according to a review published online June 6 in Pediatrics. Ayten Bilgin, Ph.D., from...
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MONDAY, June 18, 2018 -- The prevalence of obesity is higher among those living in non-metropolitan counties versus metropolitan counties, according to research published in the June 15 issue of the U.S. Centers for Disease Control and Prevention's...
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MONDAY, June 18, 2018 -- Cannabis use is associated with psychosis symptoms (PS) during adolescence, according to a research letter published online June 6 in JAMA Psychiatry. Josiane Bourque, from the University of Montreal, and colleagues examined...
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MONDAY, June 18, 2018 -- For an unselected memory clinic cohort, amyloid positron emission tomography (PET) results are associated with changes in etiology, diagnostic confidence, and patient treatment, according to a study published online June 11...
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MONDAY, June 18, 2018 -- There was an increase in Legionnaires' Disease (LD) from 2014 to 2016, according to a study published online June 15 in JAMA Network Open. Shantini D. Gamage, Ph.D., M.P.H., from the Department of Veterans Affairs (VA) in...
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MONDAY, June 18, 2018 -- Many high school students are engaged in health-risk behaviors, according to research published June 15 in the U.S. Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report. Laura Kann, Ph.D., from...
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MONDAY, June 18, 2018 -- One in three commercially available blood glucose monitor systems (BGMs) meet a predefined accuracy standard, according to research published online June 13 in Diabetes Care. David C. Klonoff, M.D., from the Diabetes...
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Retention in care and adherence to the treatment is very important for the success of the program while access for treatment is being scaled up. Without more precise data about the rate of loss to follow up as...
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Hepatitis B virus (HBV) infection is a world health problem with an estimated 257 million chronically infected people. Indonesia, with 7.1% prevalence of hepatitis B surface antigen (HBsAg), is classified as a...
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Treatment duration, treatment interval, formulation and type of antimicrobial (antibiotic) are modifiable factors that will influence antimicrobial selection pressure. Currently, the impact of the route of adm...
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This protocol describes a method for investigating the possibility of metamemory, or memory awareness, in rodents. The odor-based delayed-matching-to-sample paradigm is a novel, ecologically-relevant behavioral test useful for determining the extent to which rodents can adaptively respond based on cognitively monitoring the strength of their memory states.
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The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models—adjusting for age, sex and education—determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.
On page 5 of the article, in the last paragraph of the section "Prognostic genetic platforms: molecular phenotypes and translation to the clinic" a relevant discrepancy between the text and Table 1 could be misunderstood, therefore the paragraph was corrected
Immunology and immunotherapy of cancer is an expanding field in oncology, with recent great achievements obtained through the new successful approaches implemented to circumvent immune evasion, which is undoubtedly considered a novel hallmark of cancer. Translational research in this topic has revealed targets that can be modulated in the clinical setting with new compounds and strategies. Like most of the tumors, breast cancer is considered a complex and heterogeneous disease in which host immune responses have been also recently demonstrated of critical relevance. T infiltrating lymphocyte measurement is suggested as a powerful new tool necessary to predict early breast cancer evolution, especially for the her2-positive and triple-negative subtypes. Other biomarkers in tissue and peripheral blood are under intense scrutiny to ascertain their eventual role as prognostic and/or predictive factors. This background has fueled the interest in developing clinical research strategies to test activity of modern immunotherapy in breast cancer, which constitutes the main focus of this review.
This protocol illustrates a safe and efficient procedure to modify CD133+ hematopoietic stem cells. The presented non-viral, magnetic polyplex-based approach may provide a basis for the optimization of therapeutic stem cell effects as well as for monitoring the administered cell product via magnetic resonance imaging.
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Cue reactivity is conceptualized as sensitivity to cues linked with drug-taking experiences that contribute to craving and relapse in abstinent humans. Cue reactivity is modeled in rats by measuring attentional orientation toward drug-associated cues that results in appetitive approach behavior in a cue reactivity test following self-administration and forced abstinence.
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Warning labels that include photos linking sugary drink consumption with obesity, type 2 diabetes, and tooth decay may reduce purchases of the drinks, according to research published in Psychological Science, a journal of the Association for Psychological Science. In a field study conducted in a hospital cafeteria, researchers found that graphic warning labels reduced sugary beverage purchases by 14.8%, while text warning labels and calorie labels had no effect.
"Warning labels have been around a long time for tobacco products, but they're a new concept for sugary drinks," said study co-lead author Grant Donnelly, assistant professor of marketing at Ohio State University and former doctoral student at Harvard Business School. "Text warning labels have been passed in San Francisco and are being considered in many jurisdictions in the U.S. and around the world. Ours is the first study to evaluate the effectiveness of sugary drink warning labels in the field."
Donnelly and coauthors tested three different types of labels—text warnings and graphic warnings about the health risks of sugary drinks, and listings of the caloric value of the drinks—which they displayed near bottled and fountain beverages in a hospital cafeteria in Massachusetts. Each type of label was tested consecutively, with two-week "washout" periods between each test during which no label was displayed. More than 20,000 beverage sales were recorded during the study.
The findings showed that during the weeks when the graphic warnings were displayed, the share of sugar-sweetened beverages purchased in the cafeteria declined by 14.8%. Consumers appeared to substitute bottled water for sugary drinks; total drink sales remained constant while purchases of water increased. The average calories per drink sold also decreased during that period from 88 calories to 75. The text warnings and calorie labels did not have a significant effect on beverage purchasing.
Then, the researchers conducted two follow-up studies online. In the first, consumers were asked about how seeing a graphic warning label would influence their drink purchases. Findings showed that the graphic warnings increased negative feelings towards sugary drinks and prompted increased consideration of health risks over taste.
In the second, nationally representative online study, more than 400 participants were asked whether they would support putting the three labels on sugar-sweetened beverages. When participants were told that graphic warnings were effective at reducing sugary beverage consumption, they were equally supportive of the graphic labels warnings compared to text warnings or calorie labels.
"Sugar-sweetened beverages are the largest source of added sugars in the American diet and reducing intake of these beverages could improve population health," said co-lead author Laura Zatz, doctoral student in the Departments of Nutrition and Social and Behavioral Sciences at Harvard T.H. Chan School of Public Health. "As policymakers search for ways to reduce excess consumption of sugary drinks, graphic warning labels merit consideration as a tool that can empower consumers with salient information to encourage healthier choices."
Co-author Dan Svirsky is a doctoral student and senior author Leslie John is associate professor in the Negotiations, Organizations, and Markets Unit at Harvard Business School.
Support for this study came from Harvard University's Behavioral Insights Group and Harvard Business School. Zatz is supported by a T32 training grant (DK 007703) from the National Institutes of Health.
All data and materials have been made publicly available via the Open Science Framework (OSF). The design and analysis plans for Study 1 and Study 3 were preregistered at ClinicalTrials.gov. The design and analysis plan for Study 2 were preregistered at the OSF. The complete Open Practices Disclosure for this article are available online. This article has received badges for Open Data, Open Materials, and Preregistration.
The response to temozolomide (TMZ) treatment in small-cell lung cancer (SCLC) correlated with O(6)-methylguanine -DNA methyltransferase (MGMT) promoter methylation. 1p/19q co-deletion within oligodendroglioma is a responsive predictor for TMZ. Currently, the status of MGMT promoter methylation and 1p/19q co-deletion in pulmonary carcinoid (PC) and large-cell neuroendocrine carcinoma (LCNEC) is not reported.
Nine PC [two atypical carcinoids (AC), seven typical carcinoids (TC)] and six LCNEC patients were collected retrospectively. The pyrosequencing and fluorescence in situ hybridization were used to detect the MGMT promoter methylation and 1p/19q co-deletion in surgically resected specimens. Kaplan–Meier analysis was used to assess the rate of disease-free survival (DFS).
MGMT promoter methylation was found in two (2/6, 15.3%) LCNEC patients but not in any PC patients. Three (3/6, 50%) 1p and two (2/6, 33.3%) 19q single deletions were found in LCNEC patients. One 1p single deletion was found in AC patients. One (1/7, 14.3%) 1p and two (2/7, 28.6%) 19q single deletions were found in TC patients. After a median follow-up of 38 months, three LCNEC patients developed distant metastasis and one patient died of LCNEC disease. The DFS of PC patients was much longer than LCNEC patients (χ2 = 7.565, P = 0.006).
MGMT promoter methylation and 1p/19q co-deletion might not be the ideal biomarkers for TMZ treatment in TC/AC patients. Thus, the detection of MGMT promoter methylation and whether it can be used as a medication for TMZ in LCNEC patients necessitates investigation. Furthermore, 1p deletion could be a negative prognostic factor for LCNEC patients.
The study performed by Zhou et al. (World J Surg Oncol 15:104, 2017) titled "Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis" attempts to highlight hypoxia-inducible factor-1 alpha as a possible prognostic marker in oral squamous cell carcinoma (OSCC). We would like to underline a few points which may affect such a conclusion. The correlations between HIF-1α expression and tumour size as well as tumour stage are debatable. Further, the subgroup analysis incorporating Australia and Europe into a single subgroup limits the viability of the prognostic analysis of HIF-1α. We also suggest future studies in the same research area to analyse head and neck squamous cell carcinoma instead of OSCC, to ameliorate the limitations encountered by Zhou et al., due to the scarcity of relevant clinical data and a low number of studies about OSCC.
This study was carried out to discover the underlying role that HOXA11 plays in lung squamous cancer (LUSC) and uncover the potential corresponding molecular mechanisms and functions of HOXA11-related genes.
Twenty-three clinical paired LUSC and non-LUSC samples were utilized to examine the level of HOXA11 using quantitative real-time polymerase chain reaction (qRT-PCR). The clinical significance of HOXA11 was systematically analyzed based on 475 LUSC and 18 non-cancerous adjacent tissues from The Cancer Genome Atlas (TCGA) database. A total of 102 LUSC tissues and 121 non-cancerous tissues were available from Oncomine to explore the expressing profiles of HOXA11 in LUSC. A meta-analysis was carried out to further assess the differential expression of HOXA11 in LUSC, including in-house qRT-PCR data, expressing data extracted from TCGA and Oncomine databases. Moreover, the enrichment analysis and potential pathway annotations of HOXA11 in LUSC were accomplished via Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of hub genes and according correlations with HOXA11 were assessed to further explore the biological role of HOXA11 in LUSC.
HOXA11 expression in LUSC had a tendency to be upregulated in comparison to adjacent non-cancerous tissues by qRT-PCR. TCGA data displayed that HOXA11 was remarkably over-expressed in LUSC compared with that in non-LUSC samples, and the area under curves (AUC) was 0.955 (P < 0.001). A total of 1523 co-expressed genes were sifted for further analysis. The most significant term enriched in the KEGG pathway was focal adhesion. Among the six hub genes of HOXA11, including PARVA, ILK, COL4A1, COL4A2, ITGB1, and ITGA5, five (with the exception of COL4A1) were significantly decreased compared with the normal lung tissues. Moreover, the expression of ILK was negatively related to HOXA11 (r = − 0.141, P = 0.002).
High HOXA11 expression may lead to carcinogenesis and the development of LUSC. Furthermore, co-expressed genes might affect the prognosis of LUSC.
