Showing papers by "Southern Illinois University School of Medicine published in 2018"

Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society

Abstract: Background Consensus criteria for classifying tremor disorders were published by the International Parkinson and Movement Disorder Society in 1998. Subsequent advances with regard to essential tremor, tremor associated with dystonia, and other monosymptomatic and indeterminate tremors make a significant revision necessary. Objectives Convene an international panel of experienced investigators to review the definition and classification of tremor. Methods Computerized MEDLINE searches in January 2013 and 2015 were conducted using a combination of text words and MeSH terms: “tremor”, “tremor disorders”, “essential tremor”, “dystonic tremor”, and “classification” limited to human studies. Agreement was obtained using consensus development methodology during four in-person meetings, two teleconferences, and numerous manuscript reviews. Results Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: Axis 1—clinical characteristics, including historical features (age at onset, family history, and temporal evolution), tremor characteristics (body distribution, activation condition), associated signs (systemic, neurological), and laboratory tests (electrophysiology, imaging); and Axis 2—etiology (acquired, genetic, or idiopathic). Tremor syndromes, consisting of either isolated tremor or tremor combined with other clinical features, are defined within Axis 1. This classification scheme retains the currently accepted tremor syndromes, including essential tremor, and provides a framework for defining new syndromes. Conclusions This approach should be particularly useful in elucidating isolated tremor syndromes and syndromes consisting of tremor and other signs of uncertain significance. Consistently defined Axis 1 syndromes are needed to facilitate the elucidation of specific etiologies in Axis 2. © 2017 International Parkinson and Movement Disorder Society

Achieving Gender Equity in Physician Compensation and Career Advancement: A Position Paper of the American College of Physicians.

Abstract: Women comprise more than one third of the active physician workforce, an estimated 46% of all physicians-in-training, and more than half of all medical students in the United States. Although progress has been made toward gender diversity in the physician workforce, disparities in compensation exist and inequities have contributed to a disproportionately low number of female physicians achieving academic advancement and serving in leadership positions. Women in medicine face other challenges, including a lack of mentors, discrimination, gender bias, cultural environment of the workplace, imposter syndrome, and the need for better work-life integration. In this position paper, the American College of Physicians summarizes the unique challenges female physicians face over the course of their careers and provides recommendations to improve gender equity and ensure that the full potential of female physicians is realized.

Role of the NFκB-signaling pathway in cancer

Abstract: Cancer is a group of cells that malignantly grow and proliferate uncontrollably. At present, treatment modes for cancer mainly comprise surgery, chemotherapy, radiotherapy, molecularly targeted therapy, gene therapy, and immunotherapy. However, the curative effects of these treatments have been limited thus far by specific characteristics of tumors. Abnormal activation of signaling pathways is involved in tumor pathogenesis and plays critical roles in growth, progression, and relapse of cancers. Targeted therapies against effectors in oncogenic signaling have improved the outcomes of cancer patients. NFκB is an important signaling pathway involved in pathogenesis and treatment of cancers. Excessive activation of the NFκB-signaling pathway has been documented in various tumor tissues, and studies on this signaling pathway for targeted cancer therapy have become a hot topic. In this review, we update current understanding of the NFκB-signaling pathway in cancer.

Cerebello-cortical network fingerprints differ between essential, Parkinson's and mimicked tremors.

Abstract: Cerebello-thalamo-cortical loops play a major role in the emergence of pathological tremors and voluntary rhythmic movements. It is unclear whether these loops differ anatomically or functionally in different types of tremor. We compared age- and sex-matched groups of patients with Parkinson's disease or essential tremor and healthy controls (n = 34 per group). High-density 256-channel EEG and multi-channel EMG from extensor and flexor muscles of both wrists were recorded simultaneously while extending the hands against gravity with the forearms supported. Tremor was thereby recorded from patients, and voluntarily mimicked tremor was recorded from healthy controls. Tomographic maps of EEG-EMG coherence were constructed using a beamformer algorithm coherent source analysis. The direction and strength of information flow between different coherent sources were estimated using time-resolved partial-directed coherence analyses. Tremor severity and motor performance measures were correlated with connection strengths between coherent sources. The topography of oscillatory coherent sources in the cerebellum differed significantly among the three groups, but the cortical sources in the primary sensorimotor region and premotor cortex were not significantly different. The cerebellar and cortical source combinations matched well with known cerebello-thalamo-cortical connections derived from functional MRI resting state analyses according to the Buckner-atlas. The cerebellar sources for Parkinson's tremor and essential tremor mapped primarily to primary sensorimotor cortex, but the cerebellar source for mimicked tremor mapped primarily to premotor cortex. Time-resolved partial-directed coherence analyses revealed activity flow mainly from cerebellum to sensorimotor cortex in Parkinson's tremor and essential tremor and mainly from cerebral cortex to cerebellum in mimicked tremor. EMG oscillation flowed mainly to the cerebellum in mimicked tremor, but oscillation flowed mainly from the cerebellum to EMG in Parkinson's and essential tremor. The topography of cerebellar involvement differed among Parkinson's, essential and mimicked tremors, suggesting different cerebellar mechanisms in tremorogenesis. Indistinguishable areas of sensorimotor cortex and premotor cerebral cortex were involved in all three tremors. Information flow analyses suggest that sensory feedback and cortical efferent copy input to cerebellum are needed to produce mimicked tremor, but tremor in Parkinson's disease and essential tremor do not depend on these mechanisms. Despite the subtle differences in cerebellar source topography, we found no evidence that the cerebellum is the source of oscillation in essential tremor or that the cortico-bulbo-cerebello-thalamocortical loop plays different tremorogenic roles in Parkinson's and essential tremor. Additional studies are needed to decipher the seemingly subtle differences in cerebellocortical function in Parkinson's and essential tremors.

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Abstract: Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

Macrophage-derived Neuropilin-2 exhibits novel tumor-promoting functions

Abstract: Tumor-associated macrophages (TAM) are causally associated with tumorigenesis as well as regulation of antitumor immune responses and have emerged as potential immunotherapeutic targets. Recent evidence suggests TAM phagocytose apoptotic tumor cells within the tumor microenvironment through efferocytosis in an immunologically silent manner, thus maintaining an immunosuppressed microenvironment. The signal transduction pathways coupling efferocytosis and immunosuppression are not well known. Neuropilin-2 (NRP2) is a member of the membrane-associated neuropilin family and has been reported in different immune cells but is poorly characterized. In this study, we show that NRP2 is expressed during macrophage differentiation, is induced by tumor cells, and regulates phagocytosis in macrophages. Furthermore, NRP2 in TAM promoted efferocytosis and facilitated tumor growth. Deletion of NRP2 from TAM impaired the clearance of apoptotic tumor cells and increased secondary necrosis within tumors. This resulted in a break in the immune tolerance and reinitiated antitumor immune responses, characterized by robust infiltration of CD8+ T and natural killer cells. This result suggests NRP2 may act as a molecular mediator that connects efferocytosis and immune suppression. Deletion of NRP2 in TAM downregulated several immunosuppressive and tumor-promoting genes and upregulated immunostimulatory genes in the myeloid compartment. Taken together, our study demonstrates that TAM-derived NRP2 plays a crucial role in tumor promotion through efferocytosis, opening the enticing option for the development of effective immunotherapy targeting TAM.Significance: Neuropilin-2 in macrophages promotes tumor growth by regulating efferocytosis of apoptotic tumor cells and orchestrating immune suppression.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5600/F1.large.jpg Cancer Res; 78(19); 5600-17. ©2018 AACR.

Systematic review and meta-analysis on the efficacy and tolerability of mirabegron for the treatment of storage lower urinary tract symptoms/overactive bladder: Comparison with placebo and tolterodine.

Abstract: A systematic review and meta-analysis was carried out to evaluate the efficacy and safety of mirabegron 50 mg and 100 mg in the treatment of storage lower urinary tract symptoms/overactive bladder in comparison with a placebo and tolterodine 4 mg. A total of 491 articles were collected and eight randomized studies were identified as eligible for this meta-analysis. Overall, eight trials were included in the meta-analysis evaluating 10 248 patients. Mirabegron at both doses of 50 mg and 100 mg, and and tolterodine 4 mg were significantly associated with the reduction of incontinence episodes per 24 h, reduction of mean number of micturitions per 24 h, increase of voided volume and reduction of urgency episodes per 24 h, compared to a placebo. Both mirabegron 50 mg and mirabegron 100 mg were associated with a significant reduction of nocturia episodes when compared with a placebo. Conversely, tolterodine 4 mg did not prove to be more effective than a placebo in the reduction of nocturia episodes. Furthermore, mirabegron 50 mg showed a slightly, but significantly, better efficacy than tolterodine 4 mg in the improvement of nocturia episodes. Mirabegron 50 mg and mirabegron 100 mg shared the same risk of overall treatment-emergent adverse events rate with the placebo. Otherwise, tolterodine 4 mg was associated with a significantly greater risk than the placebo. However, mirabegron 100 mg showed a slight trend toward an increased risk of hypertension (odds ratio 1.41; P = 0.08) and cardiac arrhythmia (odds ratio 2.18; P = 0.06). Mirabegron is an effective treatment for patients with storage lower urinary tract symptoms/overactive bladder, providing a reduction of incontinence, urgency and frequency; an improvement of voided volume with a slight, but statistically, significant improvement of nocturia; with a good safety profile. These findings should be considered for the treatment planning of patients with storage lower urinary tract symptoms/overactive bladder.

Serum serotonin levels in patients with epileptic seizures

Abstract: Profound cardiovascular and/or respiratory dysfunction is part of the terminal cascade in sudden unexpected death in epilepsy (SUDEP). Central control of ventilation is mediated by brainstem rhythm generators, which are influenced by a variety of inputs, many of which use the modulatory neurotransmitter serotonin to mediate important inputs for breathing. The aim of this study was to investigate epileptic seizure-induced changes in serum serotonin levels and whether there are potential implications for SUDEP. Forty-one epileptic patients were pooled into 2 groups based on seizure type as (1) generalized tonic-clonic seizures (GTCS) of genetic generalized epilepsy and focal to bilateral tonic-clonic seizures (FBTCS; n = 19) and (2) focal seizures (n = 26) based on clinical signs using surface video-electroencephalography. Postictal serotonin levels were statistically significantly higher after GTCS and FBTCS compared to interictal levels (P = .002) but not focal seizures (P = .941). The change in serotonin (postictal-interictal) was inversely associated with a shorter duration of tonic phase of generalized seizures. The interictal serotonin level was inversely associated with a shorter period of postictal generalized electroencephalographic suppression. These data suggest that peripheral serum serotonin levels may play a role in seizure features and earlier postseizure recovery; these findings merit further study.

Exosomes in Nasopharyngeal Carcinoma.

Abstract: Exosomes are nanosized (30-100nm) membrane microvesicles secreted through a complex cellular process. Exosomes contain a variety of bioactive molecules, such as proteins, microRNAs(miRNAs or miRs) and long non-coding RNAs (lncRNAs), playing an important role in the cell-to-cell substance transportation and signal transduction. Nasopharyngeal carcinoma-related exosomes (NPC-Exo) have been identified in circulating blood and contribute to tumor cell proliferation, angiopoiesis, and immune tolerance through remodeling of tumor microenvironment (TME). Nasopharyngeal carcinoma-related exosomes may also induce epithelial-mesenchymal transition (EMT), thus promoting tumor metastasis and chemoradioresistance. Clinically, the exosomes may serve as novel biomarkers for diagnosis and targeted therapies of nasopharyngeal carcinoma. This review article updates the understanding of exosomes in nasopharyngeal carcinoma(NPC).

Cutting Edge: Elevated Leptin during Diet-Induced Obesity Reduces the Efficacy of Tumor Immunotherapy.

Abstract: Various malignancies are reproducibly cured in mouse models, but most cancer immunotherapies show objective responses in a fraction of treated patients. One reason for this disconnect may be the use of young, lean mice lacking immune-altering comorbidities present in cancer patients. Although many cancer patients are overweight or obese, the effect of obesity on antitumor immunity is understudied in preclinical tumor models. We examined the effect of obesity on two immunotherapeutic models: systemic anti-CTLA-4 mAb and intratumoral delivery of a TRAIL-encoding adenovirus plus CpG. Both therapies were effective in lean mice, but neither provided a survival benefit to diet-induced obese BALB/c mice. Interestingly, tumor-bearing leptin-deficient (ob/ob) obese BALB/c mice did respond to treatment. Moreover, reducing systemic leptin with soluble leptin receptor:Fc restored the antitumor response in diet-induced obese mice. These data demonstrate the potential of targeting leptin to improve tumor immunotherapy when immune-modulating comorbidities are present.

Cross-cultural Differences in Mental Health, Quality of Life, Empathy, and Burnout between US and Brazilian Medical Students

Abstract: This study aimed to compare mental health, quality of life, empathy, and burnout in medical students from a medical institution in the USA and another one in Brazil. This cross-cultural study included students enrolled in the first and second years of their undergraduate medical training. We evaluated depression, anxiety, and stress (DASS 21), empathy, openness to spirituality, and wellness (ESWIM), burnout (Oldenburg), and quality of life (WHOQOL-Bref) and compared them between schools. A total of 138 Brazilian and 73 US medical students were included. The comparison between all US medical students and all Brazilian medical students revealed that Brazilians reported more depression and stress and US students reported greater wellness, less exhaustion, and greater environmental quality of life. In order to address a possible response bias favoring respondents with better mental health, we also compared all US medical students with the 50% of Brazilian medical students who reported better mental health. In this comparison, we found Brazilian medical students had higher physical quality of life and US students again reported greater environmental quality of life. Cultural, social, infrastructural, and curricular differences were compared between institutions. Some noted differences were that students at the US institution were older and were exposed to smaller class sizes, earlier patient encounters, problem-based learning, and psychological support. We found important differences between Brazilian and US medical students, particularly in mental health and wellness. These findings could be explained by a complex interaction between several factors, highlighting the importance of considering cultural and school-level influences on well-being.

Drug-Induced Ototoxicity: Diagnosis and Monitoring.

Abstract: Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials.

Effects of rapamycin on growth hormone receptor knockout mice.

Abstract: It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice. In the rapamycin-treated GHR-KO mice, mTORC2 signaling was reduced without further inhibition of mTORC1 in the liver, muscle, and s.c. fat. Glucose and lipid homeostasis were impaired, and old GHR-KO mice treated with rapamycin lost functional immune cells and had increased inflammation. In GHR-KO MEF cells, knockdown of Rictor, but not Raptor, decreased mTORC2 signaling. We conclude that drastic reduction of mTORC2 plays important roles in impaired longevity in GHR-KO mice via disruption of whole-body homeostasis.

LncRNAs in DNA damage response and repair in cancer cells

Abstract: In order to maintain integrity of the genome, eukaryotic cells develop a complex DNA damage/repair response network, which can induce cell cycle arrest, apoptosis, or DNA repair. Chemo- and radiation therapies, which act primarily through the induction of DNA damage, are the most commonly used therapies for cancer. Impairment in the DNA damage response and repair system that protect cells from persistent DNA damage can affect the therapeutic efficacy of cancer. To date, accumulating evidence has suggested that long non-coding RNAs (lncRNAs) are involved in the regulation of the DNA damage/repair network. LncRNAs have been demonstrated to be master regulators of the genome at the transcriptional and post-transcriptional levels and play a key role in many physiological and pathological processes of cells. In this review, we will discuss the function of lncRNAs in regulating the cellular response to DNA damage.

Rural areas are disproportionately impacted by smoking and lung cancer

Abstract: Rural populations have higher rates of late stage lung cancer incidence and mortality compared to urban populations, making them important target populations for low dose computed tomography (LDCT) screening. LDCT screening has been shown to reduce lung cancer mortality and is recommended by the United States Preventive Services Task Force for individuals who meet certain risk criteria. However, rural populations may experience greater system, provider, and individual-level barriers to screening and related health-seeking behavior (e.g. smoking cessation). LDCT screening was first tested in urban, academic centers, so it is still unknown how readily it may be implemented in rural areas. Additionally, rural populations have limited access to both primary care physicians who may refer to LDCT screening and specialty physicians who may perform the screening. Further, rural populations may be less likely to seek screening due to lack of awareness and understanding or other unknown knowledge or psychosocial barriers. There are several strategies that may address these rural specific challenges. First, further research is needed to better understand the individual-level barriers that rural patients experience. Second, to reduce system-level barriers, additional efforts should be made to increase rural access to screening through improved referral processes. Third, creation of decision support materials to equip rural providers to engage their patients in a shared decision making process regarding screening may help reduce physician level barriers. Fourth, development of a holistic approach to smoking cessation may help reduce lung cancer risk in conjunction with LDCT screening.

The Endocannabinoid/Cannabinoid Receptor 2 System Protects Against Cisplatin-Induced Hearing Loss

Abstract: Previous studies have demonstrated the presence of cannabinoid 2 receptor (CB2R) in the rat cochlea which was induced by cisplatin. In an organ of Corti-derived cell culture model, it was also shown that an agonist of the CB2R protected these cells against cisplatin-induced apoptosis. In the current study, we determined the distribution of CB2R in the mouse and rat cochleae and examined whether these receptors provide protection against cisplatin-induced hearing loss. In a knock-in mouse model expressing the CB2R tagged with green fluorescent protein, we show distribution of CB2R in the organ of Corti, stria vascularis, spiral ligament and spiral ganglion cells. A similar distribution of CB2R was observed in the rat cochlea using a polyclonal antibody against CB2R. Trans-tympanic administration of 2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH015), a selective agonist of the CB2R, protected against cisplatin-induced hearing loss which was reversed by blockade of this receptor with 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630), an antagonist of CB2R. JWH015 also reduced the loss of outer hair cells (OHCs) in the organ of Corti, loss of inner hair cell (IHC) ribbon synapses and loss of Na+/K+-ATPase immunoreactivity in the stria vascularis. Administration of AM630 alone produced significant hearing loss (measured by auditory brainstem responses) which was not associated with loss of OHCs, but led to reductions in the levels of IHC ribbon synapses and strial Na+/K+-ATPase immunoreactivity. Furthermore, knock-down of CB2R by trans-tympanic administration of siRNA sensitized the cochlea to cisplatin-induced hearing loss at the low and middle frequencies. Hearing loss induced by cisplatin and AM630 in the rat was associated with increased expression of genes for oxidative stress and inflammatory proteins in the rat cochlea. In vitro studies indicate that JWH015 did not alter cisplatin-induced killing of cancer cells suggesting this agent could be safely used during cisplatin chemotherapy. These data unmask a protective role of the cochlear endocannabinoid/CB2R system which appears tonically active under normal conditions to preserves normal hearing. However, an exogenous agonist is needed to boost the activity of endocannabinoid/CB2R system for protection against a more traumatic cochlear insult, as observed with cisplatin administration.

Selective neck dissection in surgically treated head and neck squamous cell carcinoma patients with a clinically positive neck: Systematic review

Abstract: Adequate treatment of lymph node metastases is essential for patients with head and neck squamous cell carcinoma (HNSCC). However, there is still no consensus on the optimal surgical treatment of the neck for patients with a clinically positive (cN+) neck. In this review, we analyzed current literature about the feasibility of selective neck dissection (SND) in surgically treated HNSCC patients with cN + neck using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. From the reviewed literature, it seems that SND is a valid option in patients with cN1 and selected cN2 neck disease (non-fixed nodes, absence of palpable metastases at level IV or V, or large volume ->3 cm-multiple lymph nodes at multiple levels). Adjuvant (chemo) radiotherapy is fundamental to achieve good control rates in pN2 cases. The use of SND instead a comprehensive neck dissection (CND) could result in reduced morbidity and better functional results. We conclude that SND could replace a CND without compromising oncologic efficacy in cN1 and cN2 cases with the above-mentioned characteristics.

Comparison of the Fahn-Tolosa-Marin Clinical Rating Scale and the Essential Tremor Rating Assessment Scale.

Abstract: Background The Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) has been used in large trials for essential tremor (ET), but its anchors for ratings from 0 to 4 of upper limb tremor are probably too low for patients with severe tremor (tremor amplitude >4 cm; grade 4). The Essential Tremor Rating Assessment Scale (TETRAS) is a validated clinical scale designed specifically for the assessment of ET severity. TETRAS has anchors that span a larger range of tremor amplitudes (>20 cm = grade 4), making it more suitable for assessing patients with severe ET. However, there is no direct comparison of these scales in any clinical trial. Methods Upper limb postural and kinetic tremor items from both scales were compared using blinded, video-recorded examinations of patients with moderate-to-severe ET who participated in a trial of focused ultrasound thalamotomy. Results FTM ratings of postural and kinetic tremor correlated strongly with those of TETRAS. However, FTM exhibited a ceiling effect for severe tremor. Rest tremor, exclusive to FTM, correlated poorly with postural and kinetic tremor and had very poor test-retest reliability. In contrast, wing-beating postural tremor, exclusive to TETRAS, exhibited excellent test-retest reliability and a strong correlation with kinetic and limbs-extended-forward postural tremor. Test-retest reliabilities of the other TETRAS and FTM ratings were excellent, and both scales had good sensitivity to treatment effect. Conclusions TETRAS has 2 main advantages over FTM in the assessment of tremor severity: (1) the absence of a ceiling effect in patients with severe ET, and (2) the inclusion of wing-beating tremor.

The role of adjuvant treatment in early-stage oral cavity squamous cell carcinoma: An international collaborative study.

Abstract: BACKGROUND Up to half of patients with oral cavity squamous cell carcinoma (OCSCC) have stage I to II disease. When adequate resection is attained, no further treatment is needed; however, re-resection or radiotherapy may be indicated for patients with positive or close margins. This multicenter study evaluated the outcomes and role of adjuvant treatment in patients with stage I to II OCSCC. METHODS Overall survival (OS), disease-specific survival, local-free survival, and disease-free survival rates were calculated with Kaplan-Meier analysis. RESULTS Of 1257 patients with T1-2N0M0 disease, 33 (2.6%) had positive margins, and 205 (16.3%) had close margins. The 5-year OS rate was 80% for patients with clear margins, 52% for patients with close margins, and 63% for patients with positive margins (P 2-fold increase in the risk of recurrence (P < .0001). The multivariate analysis revealed that adjuvant treatment significantly improved the outcomes of patients with close/positive margins (P = .002 to .03). CONCLUSIONS Patients with stage I to II OCSCC and positive/close margins have poor long-term outcomes. For this population, adjuvant treatment may be associated with improved survival. Cancer 2018;124:2948-55. © 2018 American Cancer Society.

Impact of Growth Hormone-Related Mutations on Mammalian Aging.

Abstract: Mutations of a single gene can lead to a major increase in longevity in organisms ranging from yeast and worms to insects and mammals. Discovering these mutations (sometimes referred to as "longevity genes") led to identification of evolutionarily conserved molecular, cellular, and organismal mechanisms of aging. Studies in mice provided evidence for the important role of growth hormone (GH) signaling in mammalian aging. Mice with mutations or gene deletions leading to GH deficiency or GH resistance have reduced body size and delayed maturation, but are healthier and more resistant to stress, age slower, and live longer than their normal (wild type) siblings. Mutations of the same genes in people can provide remarkable protection from age-related disease, but have no consistent impact on lifespan. Ongoing research indicates that genetic defects in GH signaling are linked to extension of healthspan and lifespan via a variety of interlocking mechanism, including improvements in genome and stem cell maintenance, stress resistance, glucose homeostasis, and thermogenesis, along with reductions in the mechanistic target of rapamycin (mTOR) C1 complex signaling and in chronic low grade inflammation.

An engineered arginine-rich α-helical antimicrobial peptide exhibits broad-spectrum bactericidal activity against pathogenic bacteria and reduces bacterial infections in mice

Abstract: The increase in the prevalence of antibiotic-resistant bacteria has become a major public health concern. Antimicrobial peptides (AMPs) are emerging as promising candidates addressing this issue. In this study, we designed several AMPs by increasing α-helical contents and positive charges and optimizing hydrophobicity and amphipathicity in the Sushi 1 peptide from horseshoe crabs. A neural network–based bioinformatic prediction tool was used for the first stage evaluations of peptide properties. Among the peptides designed, Sushi-replacement peptide (SRP)-2, an arginine-rich and highly α-helical peptide, showed broad-spectrum bactericidal activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and multidrug-resistant Acinetobacter baumannii; nevertheless, it showed little hemolytic and cytotoxic activity against mammalian cells. Atomic force microscopy results indicated that SRP-2 should interact directly with cell membrane components, resulting in bacterial cell death. SRP-2 also neutralized LPS-induced macrophage activation. Moreover, in an intraperitoneal multidrug-resistant A. baumannii infection mouse model, SRP-2 successfully reduced the bacterial number in ascitic fluid and tumor necrosis factor-α production. Our study findings demonstrate that bioinformatic calculations can be powerful tools to help design potent AMPs and that arginine is superior to lysine for providing positive charges for AMPs to exhibit better bactericidal activity and selectivity against bacterial cells.