bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subbalancing Numbers
Authors: Davala Ravi Kumar , Panda G. K. 
Published: June 2018

A natural number $n$ is called balancing number (with balancer $r$)if it satisfies the Diophantine equation $1+2+\cdots+(n-1)=(n+1)+(n+2)+\cdots+(n+r).$ However, if for some pair of natural numbers $(n,r)$, $1+2+\cdots+(n-1) < (n+1)+(n+2)+\cdots+(n+r)$ and equality is achieved after adding a natural number $D$ to the left hand side then we call $n$ a $D$-subbalancing number with $D$-subbalaner number $r$. In this paper, such numbers are studied for certain values of $D$.
Clostridium difficile
Lipoprotein GerS Is Required for Cortex Modification and Thus Spore Germination
Authors: Diaz Oscar R. , Sayer Cameron V. , Popham David L. , Shen Aimee 
Published: June 2018

The Gram-positive, spore-forming bacterium
Clostridium difficile
is a leading cause of antibiotic-associated diarrhea. Because
C. difficile
is an obligate anaerobe, its aerotolerant spores are essential for transmitting disease, and their germination into toxin-producing cells is necessary for causing disease. Spore germination requires the removal of the cortex, a thick layer of modified peptidoglycan that maintains spore dormancy. Cortex degradation is mediated by the SleC hydrolase, which is thought to recognize cortex-specific modifications. Cortex degradation also requires the GerS lipoprotein for unknown reasons. In our study, we tested whether GerS is required to generate cortex-specific modifications by comparing the cortex composition of Δ
gerS
spores to the cortex composition of spores lacking two putative cortex-modifying enzymes, CwlD and PdaA. These analyses revealed that GerS, CwlD, and PdaA are all required to generate cortex-specific modifications. Since loss of these modifications in Δ
gerS
, Δ
cwlD
, and Δ
pdaA
mutants resulted in spore germination and heat resistance defects, the SleC cortex lytic enzyme depends on cortex-specific modifications to efficiently degrade this protective layer. Our results further indicate that GerS and CwlD are mutually required for removing peptide chains from spore peptidoglycan and revealed a novel interaction between these proteins. Thus, our findings provide new mechanistic insight into
C. difficile
spore germination.
Clostridium difficile
Alters the Structure and Metabolism of Distinct Cecal Microbiomes during Initial Infection To Promote Sustained Colonization
Authors: Jenior Matthew L. , Leslie Jhansi L. , Young Vincent B. , Schloss Patrick D. 
Published: June 2018

Clostridium difficile
has become the most common single cause of hospital-acquired infection over the last decade in the United States. Colonization resistance to the nosocomial pathogen is primarily provided by the gut microbiota, which is also involved in clearing the infection as the community recovers from perturbation. As distinct antibiotics are associated with different risk levels for CDI, we utilized a mouse model of infection with 3 separate antibiotic pretreatment regimens to generate alternative gut microbiomes that each allowed for
C. difficile
colonization but varied in clearance rate. To assess community-level dynamics, we implemented an integrative multi-omics approach that revealed that infection significantly changed many aspects of the gut community. The degree to which the community changed was inversely correlated with clearance during the first 6 days of infection, suggesting that
C. difficile
differentially modifies the gut environment to promote persistence. This is the first time that metagenome-enabled metatranscriptomics have been employed to study the behavior of a host-associated microbiota in response to an infection. Our results allow for a previously unseen understanding of the ecology associated with
C. difficile
infection and provide the groundwork for identification of context-specific probiotic therapies.
Premacular membrane formation after scleral buckling for primary rhegmatogenous retinal detachment: prospective study and pathophysiological insights
Authors: Cacioppo Viviana , Govetto Andrea , Radice Paolo , Virgili Gianni , Scialdone Antonio 
Published: June 2018

PurposeTo investigate the incidence, clinical features and risk factors of premacular membrane (PMM) formation after primary rhegmatogenous retinal detachment (RRD) repair with scleral buckling (SB) alone.MethodsThis institutional, prospective and consecutive case series included phakic eyes with RRD, treated with SB alone within 7 days from the occurrence of symptoms, with a follow-up of 6 months. Spectral-domain optical coherence tomography images were reviewed. The association of PMM development and morphology with preoperative and intraoperative RRD features was analysed.ResultsNinety-two patients with a mean age of 56±13 years completed the 6 months follow-up period. Postoperatively, eyes with any PMM stage were 30 out of 92 (32.6%) at 1 month and 47 out of 92 (51,1%) at both 3 months and 6 months. Over the follow-up period, 17 out of 47 PMMs (36.2%) progressed to later stages. Progression of PMMs to later stages were observed only in RRDs involving the macular region (17 out of 35 eyes, 48.5%), while none of the PMMs in macula-sparing detachments progressed to later stages (p=0.020). The risk factors significantly associated with postoperative new onset of PMM were preoperative RRDs involving the macular region (p=0.001), cryopexy time (p=0.045), presence of horseshoe tears (p=0.003), worse preoperative visual acuity (p=0.004) and subretinal fluid drainage (p=0.047).ConclusionThe incidence of postoperative PMM formation after RRD repair with SB alone was high. In retinal detachments involving the macular region PMM were more severe, tending to anatomical progression and functional deterioration. Activation of foveal Müller cell in detachments involving the macula may be a key factor in PMM progression.
Functional and aesthetic outcomes of eyelid skin grafting in facial nerve palsy
Authors: Maqsood Sundas Ejaz , Cascone Nikhil , Grixti Andre , Kannan Ruben , Nduka Charles , Malhotra Raman 
Published: June 2018

AimTo report the functional and aesthetic outcomes of eyelid full-thickness skin grafting (FTSG) in patients with facial nerve palsy (FNP).MethodsThis is a retrospective, non-comparative, single-centre review of all patients with FNP who underwent FTSG over an 8-year period. Functional outcomes were collected through case notes review: CADS (cornea, static asymmetry and dynamic and synkinesis) score facial nerve grading and lagophthalmos on blink, gentle and forced closure. Marginal reflex distance (MRD1 and MRD2) was calculated on standardised photographs. The aesthetic outcomes were assessed objectively by two blinded independent assessors who assessed standardised photographs based on a mutually agreed grading scale. Both functional and aesthetic outcomes were measured preoperatively, and at early (1–3 months), intermediate (3–6 months) and late (>9 months) postoperative periods.ResultsA total of 28 eyelid FTSGs were performed on 21 patients (11 female, 10 male) between 2008 and 2016. The mean age was 68 (range, 16–89) years and the mean follow-up was 20.8 (range, 12–30) months. The CADS score (cornea (p<0.001), static asymmetry (p<0.001), dynamic function (p<0.001)), MRD2 (p=0.002) and lagophthalmos (blink (p=0.003), gentle (p<0.001), forced (p=0.003)) improved through early and late postoperative periods. Aesthetically, the grafts appeared to look natural in terms of colour, surface contour and graft edge from the intermediate postoperative period and continued to improve significantly by the late postoperative period.ConclusionThe use of periocular FTSG is effective in improving lagophthalmos and periorbital symmetry in patients with FNP where skin contraction exists. They should be considered as an adjunct to other oculoplastic procedures for both functional and aesthetic rehabilitation.
Are medical students in prehospital care at risk of moral injury?
Authors: Murray Esther , Krahé Charlotte , Goodsman Danë 
Published: June 2018

BackgroundThe term ‘moral injury’ may be useful in conceptualising the negative psychological effects of delivering emergency and prehospital medicine as it provides a non-pathological framework for understanding these effects. This is in contrast to concepts such as burnout and post-traumatic stress disorder which suggest practitioners have reached a crisis point. We conducted an exploratory, pilot study to determine whether the concept of moral injury resonated with medical students working in emergency medicine and what might mitigate that injury for them.MethodsStructured interviews and focus groups were carried out with medical students involved in the delivery of prehospital and emergency medicine. The study was carried out at Barts and the London School of Medicine and Dentistry in May and June 2017. The data were analysed using theoretically driven thematic analysis.ResultsConcepts of moral injury such as witnessing events which contravene one’s moral code, especially those involving children, or acts of violence, resonated with the experiences of medical students in this study. Participants stated that having more medical knowledge and a clear sense of a job to do on scene helped reduce their distress at the time. While social support was a protective factor, not all students found the process of debrief easy to access or undergo, those with more established relationships with colleagues fared better in this regard.ConclusionsThe term moral injury is useful in exploring the experience of medical students in emergency medicine. More effort should be made to ensure that students effectively access debrief and other support opportunities. It is hoped that future work will be undertaken with different professional groups and explore the potential psychological and neuropsychological impact of witnessing trauma.
Neurofascin-155 IgM autoantibodies in patients with inflammatory neuropathies
Authors: Doppler Kathrin , Stengel Helena , Appeltshauser Luise , Grosskreutz Julian , Man Ng Judy King , Meinl Edgar , Sommer Claudia 
Published: June 2018

ObjectivesRecently, IgG autoantibodies against different paranodal proteins have been detected and this has led to important advances in the management of inflammatory neuropathies. In contrast, not much is known on IgM autoantibodies against paranodal proteins.MethodsIn the present study, we screened a large cohort of patients (n=140) with inflammatory neuropathies for IgM autoantibodies against neurofascin-155, neurofascin-186 or contactin-1.ResultsIgM autoantibodies against neurofascin-155 were detected by ELISA in five patients, four with inflammatory demyelinating polyradiculoneuropathy (CIDP) and one with Guillain-Barré syndrome (GBS), and were confirmed by ELISA-based preabsorption experiments and Western blot. Titres ranged from 1:100 to 1:400. We did not detect IgM anti-neurofascin-186 or anti-contactin-1 antibodies in this cohort. All patients presented with distally accentuated tetraparesis and hypesthesia. Remarkably, tremor was present in three of the patients with CIDP and occurred in the patients with GBS after the acute phase of disease. Nerve conduction studies revealed prolonged distal motor latencies and F wave latencies. Nerve biopsies showed signs of secondary axonal damage in three of the patients, demyelinating features in one patient. Teased fibre preparations did not demonstrate paranodal damage.ConclusionIn summary, IgM neurofascin-155 autoantibodies may be worth testing in patients with inflammatory neuropathies. Their pathogenic role needs to be determined in future experiments.
Loss of Estrogen-Regulated MIR135A1 at 3p21.1 Promotes Tamoxifen Resistance in Breast Cancer
Authors: Zhang Weijie , Wu Mingming , Chong Qing-Yun , Zhang Min , Zhang Xiao , Hu Lan , Zhong Yanghao , Qian Pengxu , Kong Xiangjun , Tan Sheng , Li Gaopeng , Ding Keshuo , Lobie Peter E. , Zhu Tao 
Published: June 2018

Abstract
The dysregulation of miRNAs has been increasingly recognized as a critical mediator of cancer development and progression. Here, we show that frequent deletion of the MIR135A1 locus is associated with poor prognosis in primary breast cancer. Forced expression of miR-135a decreased breast cancer progression, while inhibition of miR-135a with a specific miRNA sponge elicited opposing effects, suggestive of a tumor suppressive role of miR-135a in breast cancer. Estrogen receptor alpha (ERα) bound the promoter of MIR135A1 for its transcriptional activation, whereas tamoxifen treatment inhibited expression of miR-135a in ERα+ breast cancer cells. miR-135a directly targeted ESR1, ESRRA, and NCOA1, forming a negative feedback loop to inhibit ERα signaling. This regulatory feedback between miR-135a and ERα demonstrated that miR-135a regulated the response to tamoxifen. The tamoxifen-mediated decrease in miR-135a expression increased the expression of miR-135a targets to reduce tamoxifen sensitivity. Consistently, miR-135a expression was downregulated in ERα+ breast cancer cells with acquired tamoxifen resistance, while forced expression of miR-135a partially resensitized these cells to tamoxifen. Tamoxifen resistance mediated by the loss of miR-135a was shown to be partially dependent on the activation of the ERK1/2 and AKT pathways by miR-135a–targeted genes. Taken together, these results indicate that deletion of the MIR135A1 locus and decreased miR-135a expression promote ERα+ breast cancer progression and tamoxifen resistance.
Significance: Loss of miR-135a in breast cancer disrupts an estrogen receptor-induced negative feedback loop, perpetuating disease progression and resistance to therapy.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4915/F1.large.jpg. Cancer Res; 78(17); 4915–28. ©2018 AACR.
Enhanced Glycolysis Supports Cell Survival in EGFR-Mutant Lung Adenocarcinoma by Inhibiting Autophagy-Mediated EGFR Degradation
Authors: Kim Ji Hye , Nam Boas , Choi Yun Jung , Kim Seon Ye , Lee Jung-Eun , Sung Ki Jung , Kim Woo Sung , Choi Chang-Min , Chang Eun-Ju , Koh Jae Soo , Song Joon Seon , Yoon Shinkyo , Lee Jae Cheol , Rho Jin Kyung , Son Jaekyoung 
Published: June 2018

Abstract
Oncogenic EGFR is essential for the development and growth of non–small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes. EGFR mutation-enhanced glycolysis was required for fueling the tricarboxylic acid cycle, a critical component of EGFR stability. Nonsustained ATP production enhanced reactive oxygen species accumulation and subsequent JNK-mediated activation of autophagy, which in turn induced EGFR degradation. Our data show that EGFR-mutant NSCLCs require EGFR mutation-enhanced glycolysis to maintain EGFR stability. This pathway may serve as an attractive therapeutic target for EGFR-mutant NSCLCs.
Significance: Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC. Cancer Res; 78(16); 4482–96. ©2018 AACR.
Cotargeting Ephrin Receptor Tyrosine Kinases A2 and A3 in Cancer Stem Cells Reduces Growth of Recurrent Glioblastoma
Authors: Qazi Maleeha A. , Vora Parvez , Venugopal Chitra , Adams Jarrett , Singh Mohini , Hu Amy , Gorelik Maryna , Subapanditha Minomi K. , Savage Neil , Yang Jiahe , Chokshi Chirayu , London Max , Gont Alexander , Bobrowski David , Grinshtein Natalie , Brown Kevin R. , Murty Naresh K. , Nilvebrant Johan , Kaplan David , Moffat Jason , Sidhu Sachdev , Singh Sheila K. 
Published: June 2018

Abstract
Glioblastoma (GBM) carries a dismal prognosis and inevitably relapses despite aggressive therapy. Many members of the Eph receptor tyrosine kinase (EphR) family are expressed by GBM stem cells (GSC), which have been implicated in resistance to GBM therapy. In this study, we identify several EphRs that mark a therapeutically targetable GSC population in treatment-refractory, recurrent GBM (rGBM). Using a highly specific EphR antibody panel and CyTOF (cytometry by time-of-flight), we characterized the expression of all 14 EphR in primary and recurrent patient-derived GSCs to identify putative rGBM-specific EphR. EPHA2 and EPHA3 coexpression marked a highly tumorigenic cell population in rGBM that was enriched in GSC marker expression. Knockdown of EPHA2 and EPHA3 together led to increased expression of differentiation marker GFAP and blocked clonogenic and tumorigenic potential, promoting significantly higher survival in vivo. Treatment of rGBM with a bispecific antibody against EPHA2/A3 reduced clonogenicity in vitro and tumorigenic potential of xenografted recurrent GBM in vivo via downregulation of AKT and ERK and increased cellular differentiation. In conclusion, we show that EPHA2 and EPHA3 together mark a GSC population in rGBM and that strategic cotargeting of EPHA2 and EPHA3 presents a novel and rational therapeutic approach for rGBM.
Significance: Treatment of rGBM with a novel bispecific antibody against EPHA2 and EPHA3 reduces tumor burden, paving the way for the development of therapeutic approaches against biologically relevant targets in rGBM. Cancer Res; 78(17); 5023–37. ©2018 AACR.
The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study
Authors: Stamatopoulos Basile , Smith Thomas , Crompot Emerence , Pieters Karlien , Clifford Ruth , Mraz Marek , Robbe Pauline , Burns Adam , Timbs Adele , Bruce David , Hillmen Peter , Meuleman Nathalie , Mineur Philippe , Firescu Radu , Maerevoet Marie , De Wilde Virginie , Efira André , Philippé Jan , Verhasselt Bruno , Offner Fritz , Sims David , Heger Andreas , Dreau Hélène , Schuh Anna 
Published: June 2018

AbstractPurpose: Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21.Experimental Design: We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free survival (TFS) and overall survival (OS) in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation initiation (P &lt; 0.0001) as well as MYC target genes (P = 0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P &lt; 0.05), particularly those with IgHV mutation. In each of the three independent validation cohorts, we showed that IgLV3-21 rearrangements—similar to UM IgHV status—conferred poor prognosis compared with mutated IgHV (P &lt; 0.0001). Importantly, we confirmed by multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P &lt; 0.0001).Conclusions: We have demonstrated for the first time that a light chain can affect CLL prognosis and that IgLV3-21 light chain usage defines a new subgroup of CLL patients with poor prognosis. Clin Cancer Res; 24(20); 5048–57. ©2018 AACR.
Prognostic Indicators in Stage IV Surgically Treated Gastric Cancer Patients: A Retrospective Multi-Institutional Study
Authors: Biondi Alberto , D’Ugo Domenico , Cananzi Ferdinando , Rausei Stefano , Sicoli Federico , Santullo Francesco , Laurino Antonio , Ruspi Laura , Belia Francesco , Quagliuolo Vittorio , Persiani Roberto 
Published: June 2018

<b><i>Introduction:</i></b> The role of gastric resection in treating metastatic gastric adenocarcinoma is controversial. In the present study, we reviewed the short- and long-term outcomes of stage IV patients undergoing surgery. <b><i>Methods:</i></b> A retrospective review was conducted that assessed patients undergoing elective surgery for incurable gastric carcinoma. Short- and long-term results were evaluated. <b><i>Results:</i></b> A total of 122 stage IV gastric cancer patients were assessed. Postoperative mortality was 5.7%, and the overall rate of complications was 35.2%. The overall survival rate at 1 and 3 years was 58 and 19% respectively; the median survival was 14 months. Improved survival was observed for the factors age less than 60 years (<i>p</i> = 0.015), site of metastases (<i>p</i> = 0.022), extended lymph node dissection (<i>p</i> = 0.044), absence of residual disease after surgery (<i>p</i> = 0.001), and administration of adjuvant chemotherapy (<i>p</i> = 0.016). Multivariate analysis showed that residual disease and adjuvant chemotherapy were independent prognostic factors. <b><i>Conclusions:</i></b> The results of this study suggest that surgery combined with systemic chemotherapy in selected patients with stage IV gastric cancer can improve survival.