Deep imaging: How much of the proteome does current top-down technology already resolve?

Effective proteome analyses are based on interplay between resolution and detection. It had been claimed that resolution was the main factor limiting the use of two-dimensional gel electrophoresis. Improved protein detection now indicates that this is unlikely to be the case. Using a highly refined protocol, the rat brain proteome was extracted, resolved, and detected. In order to overcome the stain saturation threshold, high abundance protein species were excised from the gel following standard imaging. Gels were then imaged again using longer exposure times, enabling detection of lower abundance, less intensely stained protein species. This resulted in a significant enhancement in the detection of resolved proteins, and a slightly modified digestion protocol enabled effective identification by standard mass spectrometric methods. The data indicate that the resolution required for comprehensive proteome analyses is already available, can assess multiple samples in parallel, and preserve critical information concerning post-translational modifications. Further optimization of staining and detection methods promises additional improvements to this economical, widely accessible and effective top-down approach to proteome analysis. © 2014 Wright et al

Cancer drug approvals that displaced existing standard-of-care therapies, 2016-2021

Importance Although several cancer drugs receive US Food and Drug Administration (FDA) approval each month, it is unclear how many of these cancer drugs transform the treatment landscape significantly by tumor group. Specifically, it remains unclear how many of these newly approved cancer drugs displace the existing standard-of-care therapies for their indication vs being added to existing therapies. Objective To examine how many cancer drugs displace the standard-of-care therapies vs being added to existing therapy or filling breaks in systemic treatments in the metastatic setting, adjuvant setting, or maintenance setting. Design, Setting, and Participants Retrospective cross-sectional study using landmark trials leading to FDA approval of cancer drugs between May 1, 2016, and May 31, 2021. The study evaluated all FDA approvals for cancer drugs between May 1, 2016, and May 31, 2021, using the FDA Oncology (Cancer)/Hematologic Malignancies Approval Notifications website. All clinical trials leading to FDA approval of cancer drugs during this period were examined. Main Outcomes and Measures A drug was determined to have displaced the prior standard-of-care therapy by evaluating the comparator arm (or lack thereof) in the clinical trial leading to the drug’s approval and also by reviewing National Comprehensive Cancer Network Guidelines. Cancer drug approvals were categorized as first-line displacing if a drug was approved for use in the first-line setting and displaced the prior standard-of-care drug for an indication, first-line drug alternatives/new if a drug was approved for use in the first-line setting but did not displace the standard of care at the time of approval or was a new drug that was first of its class for an approved indication, add on if a drug was approved in combination with a previously approved therapy for a disease or if a drug was approved for use in the adjuvant or maintenance settings, and later line if a drug was approved for use in the second-, third-, or later-line settings. Results Between May 1, 2016, and May 31, 2021, there were 207 FDA cancer drug approvals in oncology and malignant hematology. Of these 207 approvals, 28 drugs (14%) were first-line displacing therapies. A total of 32 drugs (15%) were first-line drug alternatives/new drugs. A total of 61 drugs (29%) were add-on therapies. Finally, 86 drugs (42%) were approved as later-line therapies. Conclusions and Relevance In this study, most cancer drug approvals between 2016 and 2021 were in the later-line settings as opposed to displacing the current standard-of-care therapy for the approved indication. These later-line drugs may benefit patients with few alternatives but add to the cost of care because competition in the drug markets is a key factor in leading to lower drug prices

Schwannoma of the external auditory canal: a case report

BACKGROUND: Schwannomas are uncommon benign tumors of the external auditory canal. The clinical features, the differential diagnosis, and the surgical treatment of these lesions are discussed. CASE PRESENTATION: A 51-year-old patient presented with a mass obliterating the external auditory meatus. Excisional biopsy was performed. Diagnosis was reported to be schwannoma by histopathologic examination. CONCLUSION: Schwannoma, rarely seen in the external auditory canal, can be managed by a precise excision of the tumor via transmeatal approach

Association between mid-wall late gadolinium enhancement and sudden cardiac death in patients with dilated cardiomyopathy and mild and moderate left ventricular systolic dysfunction

Background—Current guidelines only recommend the use of an implantable cardioverter defibrillator (ICD) in patients with dilated cardiomyopathy (DCM) for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF)35%. Patients with a LVEF>35% also have low competing risks of death from non-sudden causes. Therefore, those at high-risk of SCD may gain longevity from successful ICD therapy. We investigated whether late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) identified patients with DCM without severe LV systolic dysfunction at high-risk of SCD. Methods—We prospectively investigated the association between mid-wall late gadolinium enhancement (LGE) and the pre-specified primary composite outcome of SCD or aborted SCD amongst consecutive referrals with DCM and a LVEF≥40% to our center between January 2000 and December 2011, who did not have a pre-existing indication for ICD implantation. Results—Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the pre-specified end-point, compared to 7 of 298 (2.3%) without (HR 9.2; 95% CI 3.9-21.8; p5% compared to those without LGE were 10.6 (95%CI 3.9-29.4), 4.9 (95% CI 1.3-18.9) and 11.8 (95% CI 4.3-32.3) respectively. Conclusions—Mid-wall LGE identifies a group of patients with DCM and LVEF≥40% at increased risk of SCD and low-risk of non-sudden death who may benefit from ICD implantation

A weak group inverse for rectangular matrices

[EN] In this paper, we extend the notion of weak group inverse to rectangular matrices (called WweightedWGinverse) by using the weighted core EP inverse recently investigated. This new generalized inverse also generalizes the well-known weighted group inverse given by Cline and Greville. In addition, we give several representations of the W-weighted WG inverse, and derive some characterizations and properties.First author was partially supported by UNRC (Grant PPI 18/C472) and CONICET (Grant PIP 112-201501-00433CO). Third author was partially supported by Ministerio de Economia, Industria y Competitividad of Spain (Grants DGI MTM2013-43678-P and Red de Excelencia MTM2017-90682-REDT).Ferreyra, DE.; Orquera, V.; Thome, N. (2019). A weak group inverse for rectangular matrices. Revista de la Real Academia de Ciencias Exactas Físicas y Naturales Serie A Matemáticas. 113(4):3727-3740. https://doi.org/10.1007/s13398-019-00674-9S372737401134Ben-Israel, A., Greville, T.N.E.: Generalized Inverses: Theory and Applications, 2nd edn. Springer, New York (2003)Baksalary, O.M., Trenkler, G.: Core inverse of matrices. Linear Multilinear Algebra 58, 681–697 (2010)Baksalary, O.M., Trenkler, G.: On a generalized core inverse. Appl. Math. Comput. 236, 450–457 (2014)Bajodah, A.H.: Servo-constraint generalized inverse dynamics for robot manipulator control design. Int. J. Robot. Autom. 25, (2010). https://doi.org/10.2316/Journal.206.2016.1.206-3291Campbell, S.L., Meyer Jr., C.D.: Generalized Inverses of Linear transformations. SIAM, Philadelphia (2009)Cline, R.E., Greville, T.N.E.: A Drazin inverse for rectangular matrices. Linear Algebra Appl. 29, 53–62 (1980)Dajić, A., Koliha, J.J.: The weighted g-Drazin inverse for operators. J. Aust. Math. Soc. 2, 163–181 (2007)Doty, K.L., Melchiorri, C., Bonivento, C.: A theory of generalized inverses applied to robotics. Int. J. Rob. Res. 12, 1–19 (1993)Drazin, M.P.: Pseudo-inverses in associate rings and semirings. Am. Math. Mon. 65, 506–514 (1958)Ferreyra, D.E., Levis, F.E., Thome, N.: Revisiting of the core EP inverse and its extension to rectangular matrices. Quaest. Math. 41, 265–281 (2018)Ferreyra, D.E., Levis, F.E., Thome, N.: Maximal classes of matrices determining generalized inverses. Appl. Math. Comput. 333, 42–52 (2018)Gigola, S., Lebtahi, L., Thome, N.: The inverse eigenvalue problem for a Hermitian reflexive matrix and the optimization problem. J. Comput. Appl. Math. 291, 449–457 (2016)Hartwig, R.E.: The weighted $$*$$ ∗ -core-nilpotent decomposition. Linear Algebra Appl. 211, 101–111 (1994)Kirkland, S.J., Neumann, M.: Group inverses of M-matrices and their applications. Chapman and Hall/CRC, London (2013)Malik, S., Thome, N.: On a new generalized inverse for matrices of an arbitrary index. Appl. Math. Comput. 226, 575–580 (2014)Male $${{\check{\rm s}}}$$ s ˇ ević, B., Obradović, R., Banjac, B., Jovović, I., Makragić, M.: Application of polynomial texture mapping in process of digitalization of cultural heritage. arXiv:1312.6935 (2013). Accessed 14 June 2018Manjunatha Prasad, K., Mohana, K.S.: Core EP inverse. Linear Multilinear Algebra 62, 792–802 (2014)Mehdipour, M., Salemi, A.: On a new generalized inverse of matrices. Linear Multilinear Algebra 66, 1046–1053 (2018)Meng, L.S.: The DMP inverse for rectangular matrices. Filomat 31, 6015–6019 (2017)Mosić, D.: The CMP inverse for rectangular matrices. Aequaetiones Math. 92, 649–659 (2018)Penrose, R.: A generalized inverse for matrices. Proc. Cambrid. Philos. Soc. 51, 406–413 (1955)Soleimani, F., Stanimirović, P.S., Soleymani, F.: Some matrix iterations for computing generalized inverses and balancing chemical equations. Algorithms 8, 982–998 (2015)Xiao, G.Z., Shen, B.Z., Wu, C.K., Wong, C.S.: Some spectral techniques in coding theory. Discrete Math. 87, 181–186 (1991)Wang, H.: Core-EP decomposition and its applications. Linear Algebra Appl. 508, 289–300 (2016)Wang, H., Chen, J.: Weak group inverse. Open Math. 16, 1218–1232 (2018)Wei, Y.: A characterization for the $$W$$ W -weighted Drazin inverse and a Crammer rule for the $$W$$ W -weighted Drazin inverse solution. Appl. Math. Comput. 125, 303–310 (2002

Cardiorespiratory fitness, fatness and the acute blood pressure response to exercise in adolescence

Objective: Exaggerated exercise blood pressure (BP) is associated with cardiovascular risk factors in adolescence. Cardiorespiratory fitness and adiposity (fatness) areindependent contributors to cardiovascular risk, but their interrelated associationswith exercise BP are unknown. This study aimed to determine the relationships between fitness, fatness, and the acute BP response to exercise in a large birth cohort ofadolescents.Methods: 2292 adolescents from the Avon Longitudinal Study of Parents andChildren (aged 17.8 ± 0.4 years, 38.5% male) completed a sub-maximal exercisestep test that allowed fitness (VO2 max) to be determined from workload and heart rateusing a validated equation. Exercise BP was measured immediately on test cessationand fatness calculated as the ratio of total fat mass to total body mass measured byDXA.Results: Post-exercise systolic BP decreased stepwise with tertile of fitness (146(18); 142 (17); 141 (16) mmHg) but increased with tertile of fatness (138 (15); 142(16); 149 (18) mmHg). In separate models, fitness and fatness were associated withpost-exercise systolic BP adjusted for sex, age, height, smoking, and socioeconomicstatus (standardized β: −1.80, 95%CI: −2.64, −0.95 mmHg/SD and 4.31, 95%CI:3.49, 5.13 mmHg/SD). However, when fitness and fatness were included in thesame model, only fatness remained associated with exercise BP (4.65, 95%CI: 3.69,5.61 mmHg/SD).Conclusion: Both fitness and fatness are associated with the acute BP response to exercise in adolescence. The fitness-exercise BP association was not independent of fatness, implying the cardiovascular protective effects of cardiorespiratory fitness mayonly be realized with more favorable body composition

Linking Proteins to Signaling Pathways for Experiment Design and Evaluation

Biomedical experimental work often focuses on altering the functions of selected proteins. These changes can hit signaling pathways, and can therefore unexpectedly and non-specifically affect cellular processes. We propose PathwayLinker, an online tool that can provide a first estimate of the possible signaling effects of such changes, e.g., drug or microRNA treatments. PathwayLinker minimizes the users' efforts by integrating protein-protein interaction and signaling pathway data from several sources with statistical significance tests and clear visualization. We demonstrate through three case studies that the developed tool can point out unexpected signaling bias in normal laboratory experiments and identify likely novel signaling proteins among the interactors of known drug targets. In our first case study we show that knockdown of the Caenorhabditis elegans gene cdc-25.1 (meant to avoid progeny) may globally affect the signaling system and unexpectedly bias experiments. In the second case study we evaluate the loss-of-function phenotypes of a less known C. elegans gene to predict its function. In the third case study we analyze GJA1, an anti-cancer drug target protein in human, and predict for this protein novel signaling pathway memberships, which may be sources of side effects. Compared to similar services, a major advantage of PathwayLinker is that it drastically reduces the necessary amount of manual literature searches and can be used without a computational background. PathwayLinker is available at http://PathwayLinker.org. Detailed documentation and source code are available at the website

Mortality among Patients with Cleared Hepatitis C Virus Infection Compared to the General Population: A Danish Nationwide Cohort Study

BACKGROUND: The increased mortality in HCV-infected individuals partly stems from viral damage to the liver and partly from risk-taking behaviours. We examined mortality in patients who cleared their HCV-infection, comparing it to that of the general population. We also addressed the question whether prognosis differed according to age, substance abuse (alcohol abuse and injection drug use) and comorbidity. METHODOLOGY/PRINCIPAL FINDINGS: Patients with cleared HCV-infection were categorized into one of 8 groups according to age (20-39 years or 40-69 years) and patient characteristics (no substance abuse/no comorbidity; substance abuse/no comorbidity; no substance abuse/comorbidity; and substance abuse/comorbidity). For each patient, 4 age- and gender-matched individuals without substance abuse or comorbidity were selected from the general population, comprising a total of 8 comparison cohorts. We analyzed 10-year survival and used stratified Cox Regression analysis to compute mortality rate ratios (MRRs), comparing mortality between the 8 patient groups and the comparison cohorts, adjusting for personal income. Among patients without substance abuse or comorbidity, those aged 40-69 years had the same mortality as the comparison cohort (10-year survival: 95% (95% confidence interval [CI]: 93%-97%), MRR: 1.3 (95% CI: 0.8-2.3)), whereas those aged 20-39 years had higher mortality than the comparison cohort (10-year survival: 93% versus 99%, MRR: 5.7 (95% CI: 2.3-14.0). For both age categories, substance abuse and comorbidity decreased survival and increased MRRs. Patients aged 40-69 years with substance abuse and comorbidity suffered from substantial mortality (MRR: 12.5 (95% CI: 5.1-30.6)). CONCLUSIONS: Mortality in patients aged 40-69 years with cleared HCV-infection is comparable to individuals without HCV, provided they have no substance abuse or comorbidity. Any substance abuse and/or comorbidity not captured in the registries used for our study could explain the increased mortality in patients aged 20-39 years without documented substance abuse or comorbidity

The Internally Truncated LRP5 Receptor Presents a Therapeutic Target in Breast Cancer

BACKGROUND: Breast cancer is a common malignant disease, which may be caused by a number of genes deregulated by genomic or epigenomic events. Deregulated WNT/beta-catenin signaling with accumulation of beta-catenin is common in breast tumors, but mutations in WNT signaling pathway components have been rare. An aberrantly spliced internally truncated LRP5 receptor (LRP5Delta666-809, LRP5Delta) was shown recently to be resistant to DKK1 inhibition, and was required for beta-catenin accumulation in hyperparathyroid tumors and parathyroid tumor growth. METHODOLOGY/PRINCIPAL FINDINGS: Here we show, by reverse transcription PCR and Western blot analysis, that LRP5Delta is frequently expressed in breast tumors of different cancer stage (58-100%), including carcinoma in situ and metastatic carcinoma. LRP5Delta was required in MCF7 breast cancer cells for the non-phosphorylated active beta-catenin level, transcription activity of beta-catenin, cell growth in vitro, and breast tumor growth in a xenograft SCID mouse model. WNT3 ligand, but not WNT1 and WNT3A augmented the endogenous beta-catenin activity of MCF7 cells in a DKK1-insensitive manner. Furthermore, an anti-LRP5 antibody attenuated beta-catenin activity, inhibited cell growth, and induced apoptosis in LRP5Delta-positive MCF7 and T-47D breast cancer cells, but not in control cells. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the LRP5Delta receptor is strongly implicated in mammary gland tumorigenesis and that its aberrant expression present an early event during disease progression. LRP5 antibody therapy may have a significant role in the treatment of breast cancer

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty