tbuckley/cabot-search huggingface dataset:
Clinical utility of serum Ca 15–3 and CEA in monitoring advanced breast cancer patients undergoing trastuzumab-based therapy
Authors: R. Duchnowska, M. Miedzinska-Maciejewska, M. Konieczna, I. Pietrzak, C. Szczylik
Journal: Journal of Clinical Oncology (2005)

766 Background: The clinical usefulness of serum Ca15–3 and CEA in advanced breast cancer patients administered systemic therapy is debatable. There are particularly few data on the relevance of these tests in patients applied trastuzumab. We evaluated retrospectively the relationship between Ca 15–3 and CEA serum levels, and treatment outcome during trastuzumab therapy. Material and Methods: Study group included 43 patients (median age 50 years; range 31–71 years) with recurrent or advanced HER2/neu overexpressing breast cancer who were administered trastuzumab with or without additional systemic therapies. Serum levels of CEA and Ca 15–3 were measured prior to initiation of therapy and every 3 months during treatment. Samples were tested using ELISA assays. Ca 15–3 and CEA values below 30 U/ml and 5 ng/ml, respectively were considered normal. 36 patients were evaluable for this analysis, of whom 22 (61%) responded to treatment. The median follow-up in the entire group was 9 months (range 3 to 24 months). Results: Baseline Ca 15–3 and CEA levels were elevated in 62% and 48% patients, respectively. Changes in serum levels of both markers during therapy did not predict for relapse (concordance with progression at 3, 6, 9 and 12 months for CA 15–3 and CEA as single tests was 0.29 and 0.20; 0.17 and 0.64; 0.46 and 0.26; 0.00 and 0.16). Combined analysis of CEA and CA 15–3 did not increase their predictive value. Conclusion: These results suggest limited clinical usefulness of serum Ca 15–3 and CEA, considered as single tests or in combination, in monitoring trastuzumab therapy in advanced breast cancer patients. No significant financial relationships to disclose.
Neuronal toll-like receptor (TLR) 7 expression and function in human airways
Authors: Matthew Drake, Gregory Scott, Elad Kaufman, Allison Fryer, David Jacoby
Journal: European Respiratory Journal (2014)

BACKGROUND : TLR7 detects viral single-stranded RNA and triggers an innate immune response. We recently showed that TLR7 agonists relax guinea pig, mouse, and human airways within seconds. We investigated TLR7 expression and signaling in post-mortem human airways.

METHODS : Human trachea and primary bronchi were immunostained with anti-TLR7 antibodies, neuronal marker PGP9.5 and nuclear stain DAPI, and were imaged by confocal microscopy (20X, 63X; 1.4 numerical aperture). TLR7 function was assessed in human airway strips suspended in an organ bath. Airways were contracted with methacholine (10 µM) and exposed to TLR7 agonist (R837; 10-300 µM). Some airways were pretreated with the TLR7 antagonist (IRS661; 100 µM) or nitric oxide synthase inhibitor (L-NMMA; 100 µM).

RESULTS : TLR7 (labeled yellow) was expressed on airway nerves (labeled red), but not airway smooth muscle (labeled blue). TLR7 was expressed on nerve cell bodies located within the airway wall, consistent with parasympathetic nerve distribution. TLR7 agonist caused dose-dependent relaxation of pre-contracted human airways that was blocked by the TLR7 antagonist IRS661, and by inhibition of nitric oxide synthase.

![Figure][1] 



CONCLUSIONS : Neuronal TLR7 expression suggests airway nerves have a novel role in the immune response to respiratory viruses, and can induce bronchorelaxation via the production of nitric oxide.

 [1]: pending:yes
ETIOLOGY OF THE VARIOUS DEFORMITIES OF HIP-JOINT DISEASE.
Journal: JAMA (1893)

In the transactions of the American Orthopedic Association, vol. v., a new theory for the causation of the deformities of hip disease is advanced byDr. A. M. Phelps, of New York. Heretofore it has been held that the deformities of flexion, abduction and adduction were caused either by the limit assuming the position of greatest comfort, or that flexion and adduction at the commencement of the disease were due to the joint capsule being distended with fluid, and later when the capsule ruptured, the limb passed into adduction and greater flexion because the adductors and flexors were stronger than the abductors and extensors. Neither theory has been satisfactory. From abundant clinical dataDr. Phelpsfound: 1. That abduction always preceded flexion, or was attended by it, in the first stage; 2. That abduction and outward rotation are always present in the second stage, and flexion nearly always present, but
Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis
Authors: Andrew G Renehan, Lee Malcomson, Richard Emsley, Simon Gollins, Andrew Maw, Arthur Sun Myint, Paul S Rooney, Shabbir Susnerwala, Anthony Blower, Mark P Saunders, Malcolm S Wilson, Nigel Scott, Sarah T O'Dwyer
Journal: The Lancet Oncology (2015)
Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies
Authors: Christof M. Kazda, Ying Ding, Ronan P. Kelly, Parag Garhyan, Chunxue Shi, Chay Ngee Lim, Haoda Fu, David E. Watson, Andrew J. Lewin, William H. Landschulz, Mark A. Deeg, David E. Moller, Thomas A. Hardy
Journal: Diabetes Care (2015)

OBJECTIVE Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks. RESULTS LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was –0.83% (10 mg), –0.65% (30 mg), and –0.66% (60 mg) (all P &amp;lt; 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was –0.45% (2.5 mg), –0.78% (10 mg, P &amp;lt; 0.05), –0.92% (20 mg, P &amp;lt; 0.05), and –0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo. CONCLUSIONS In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.
Tyrosine-Dependent and -Independent Mechanisms of STAT3 Activation by the Human Granulocyte Colony-Stimulating Factor (G-CSF) Receptor Are Differentially Utilized Depending on G-CSF Concentration
Authors: Alister C. Ward, Mirjam H.A. Hermans, Louise Smith, Yvette M. van Aesch, Anita M. Schelen, Claudia Antonissen, Ivo P. Touw
Journal: Blood (1999)
Two Phase III Studies Evaluating Ceritinib in Patients (Pts) with Anaplastic Lymphoma Kinase (Alk)-Rearranged (Alk+) Non-Small Cell Lung Cancer (Nsclc): Ascend-4 and Ascend-5
Authors: A. Shaw, D.S.W. Tan, L. Crinò, E. Felip, T.S.K. Mok, M. Nishio, L. Paz-Ares, G. Scagliotti, D.R. Spigel, J. Wolf, Y. Wu, G. Castro, P. Sen, C. Zheng, A. Joe, J-C Soria
Journal: Annals of Oncology (2014)
Toward a Molecular Understanding of the Antibacterial Mechanism of Copper‐Bearing Titanium Alloys against <i>Staphylococcus aureus</i>
Authors: Mei Li, Zheng Ma, Ye Zhu, Hong Xia, Mengyu Yao, Xiao Chu, Xiaolan Wang, Ke Yang, Mingying Yang, Yu Zhang, Chuanbin Mao
Journal: Advanced Healthcare Materials (2015)

The antibacterial mechanism of the Cu‐containing materials has not been fully understood although such understanding is crucial for the sustained clinical use of Cu‐containing antibacterial materials such as bone implants. The aim of this study is to investigate the molecular mechanisms by which the Gram‐positive Staphylococcus aureus is inactivated through Cu‐bearing titanium alloys (Ti6Al4V5Cu). Cu ions released from the alloys are found to contribute to lethal damage of bacteria. They destroy the permeability of the bacterial membranes, resulting in the leakage of reducing sugars and proteins from the cells. They also promote the generation of bacteria‐killing reactive oxygen species (ROS). The ROS production is confirmed by several assays including fluorescent staining of intracellular oxidative stress, detection of respiratory chain activity, and measurement of the levels of lipid peroxidation, catalase, and glutathione. Furthermore, the released Cu ions show obvious genetic toxicity by interfering the replication of nuc (species‐specific) and 16SrRNA genes, but with no effect on the genome integrity. All of these effects lead to the antibacterial effect of Ti6Al4V5Cu. Collectively, our work reconciles the conflicting antibacterial mechanisms of Cu‐bearing metallic materials or nanoparticles reported in the literature and highlights the potential use of Ti6Al4V5Cu alloys in inhibiting bacterial infections.
Twice-Weekly Oral MLN9708 (Ixazomib Citrate), An Investigational Proteasome Inhibitor, In Combination With Lenalidomide (Len) and Dexamethasone (Dex) In Patients (Pts) With Newly Diagnosed Multiple Myeloma (MM): Final Phase 1 Results and Phase 2 Data
Authors: Paul G. Richardson, Craig C Hofmeister, Cara A Rosenbaum, Myo Htut, David H. Vesole, Jesus Berdeja, Michaela Liedtke, Ajai Chari, Stephen D Smith, Daniel Lebovic, Deborah Berg, Eileen Liao, Neeraj Gupta, Alessandra Di Bacco, Jose Estevam, Ai-Min Hui, Rachid Baz
Journal: Blood (2013)
Corrigendum to “De-escalation therapy among bacteraemic patients with community-acquired pneumonia” [Clin Microbiol Infect 21 (2015) 936.e11–936.e18]
Authors: M. Carugati, F. Franzetti, T. Wiemken, R.R. Kelley, P. Peyrani, F. Blasi, J. Ramirez, S. Aliberti
Journal: Clinical Microbiology and Infection (2015)
Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron
Authors: Jiandong Zhang, Nathan P. Rudemiller, Mehul B. Patel, Norah S. Karlovich, Min Wu, Alicia A. McDonough, Robert Griffiths, Matthew A. Sparks, Alexander D. Jeffs, Steven D. Crowley
Journal: Cell Metabolism (2015)
Rotating magnetic field induced oscillation of magnetic particles for in vivo mechanical destruction of malignant glioma
Authors: Yu Cheng, Megan E. Muroski, Dorothée C.M.C. Petit, Rhodri Mansell, Tarun Vemulkar, Ramin A. Morshed, Yu Han, Irina V. Balyasnikova, Craig M. Horbinski, Xinlei Huang, Lingjiao Zhang, Russell P. Cowburn, Maciej S. Lesniak
Journal: Journal of Controlled Release (2015)
The effect of SGN-75, a novel antibody–drug conjugate (ADC), in treatment of patients with renal cell carcinoma (RCC) or non-Hodgkin lymphoma (NHL): A phase I study.
Authors: J. A. Thompson, A. Forero-Torres, E. I. Heath, S. M. Ansell, S. K. Pal, J. R. Infante, S. De Vos, P. A. Hamlin, B. Zhao, K. Klussman, N. C. Whiting
Journal: Journal of Clinical Oncology (2011)

3071 Background: SGN-75 is an ADC composed of a humanized anti-CD70 mAb conjugated to the antimicrotubule agent MMAF, via a plasma-stable linker. Upon binding to CD70, SGN-75 internalizes and releases cys‐mcMMAF, which binds tubulin and induces G2/M arrest and apoptosis. Methods: A phase I, dose-escalation, multicenter study was initiated to investigate the safety, tolerability, PK, pharmacodynamic effects, and antitumor activity of SGN-75 monotherapy in pts with CD70-positive metastatic RCC or relapsed/refractory NHL. SGN-75 was administered IV in cohort-specific doses using 2 schedules (q3wk or q1wk). Pts were eligible to receive cycles of SGN-75 until progression. Results: A total of 26 pts, 14 RCC and 12 NHL, have been treated. Median age was 60 years (range 30–70); all pts had an ECOG status of 0/1. RCC pts had a median 3.5 prior regimens (range 1–7), and all had prior nephrectomy. NHL pts had a median 3 prior regimens (range 1–6), and 2 had prior autoSCT. Doses up to 3 mg/kg q3wk and 0.6 mg/kg q1wk have been tolerated; MTD has not been reached in either dosing schedule. The most common AEs were fatigue (31%), nausea (23%), dyspnea, peripheral edema, and thrombocytopenia (19% each). AEs ≥ Gr 3 observed in >1 pt were thrombocytopenia, dyspnea, and fatigue (3, 2, and 2 pts). Related serious AEs were Gr 2 iridocyclitis and Gr 4 ITP. Preliminary PK analysis demonstrated dose-proportional exposure; mean SGN-75 terminal half-life ranged from 6–13 days across dose levels. Best responses in RCC were 2 PR, 5 SD, 6 PD, and 1 not evaluated (NE); in NHL, responses were 1 CR, 6 SD, 3 PD, and 2 NE. Objective responses were observed at 1 mg/kg q3wk (CR - mantle cell lymphoma; 31 wk duration), 2 mg/kg q3wk (PR - RCC; 7+ wk duration), and 3 mg/kg q3wk (PR - RCC; 2+ days duration). CD70 expression was variable among all patients; the 3 responding pts had nearly uniform CD70 expression on malignant cells. Conclusions: SGN-75 has generally been well tolerated in pts with RCC or NHL; MTD has not been reached in 2 dosing schedules under investigation, and dose escalation is ongoing. Encouraging antitumor activity has been observed in both heavily pretreated RCC pts and in relapsed/refractory NHL pts.
Development of anti-GPC-1 (glypican-1)-CAR-T cells for adoptive T cell immunotherapies for squamous cell carcinoma
Authors: Tomonori Yaguchi, Kenji Morii, Satoshi Serada, Tetsuji Naka, Yutaka Kawakami
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immunotherapies using T cells transduced with a chimeric antigen receptor (CAR) gene have been demonstrated as a promising strategy for cancer treatment. CAR-T cells can specifically recognize tumor antigen expressed on the cell surface and eliminate tumors. Although CAR-T cell
Abstract 11957: Impact of Post Dilatation on the One-Year Clinical Outcomes of a Large Cohort of Patients Treated Solely With the Absorb Bioresorbable Vascular Scaffold
Authors: Jose de Ribamar Costa, Alexandre Abizaid, Antonio Bartorelli, Robert Jan van Geuns, Ashok Seth, Patrick Serruys
Journal: Circulation (2014)

Background: Although bioresorbable scaffolds (BRS) may have important benefits, their deployment requires more aggressive lesion preparation compared to the best metallic DES due to different radial force and crossing profile. In addition, the benefits of post dilatation (PD) have not been systematically studied, with reports of fracture if the BRS expansion limits are exceeded by excessive PD. We sought to determine the impact of PD on clinical outcomes in a large cohort of patients treated with the Absorb only. Methods: We evaluated all consecutive patients enrolled in the multicenter, single arm ABSORB EXTEND Study through June 2013. The study allowed treatment of up to 2 coronaries (diameter 2.0 to 3.8mm) and the use of overlapping (lesion length ≤ 28mm). Patients with severe lesion calcification/tortuosity were excluded. Aggressive lesion pre dilatation (balloon to artery ratio of 0.9-1.0) was mandatory and PD was left to the operator’s discretion (if performed, non-compliant balloons up to 0.5mm lar...
Why Does the Weeping Willow Weep? Reconceptualizing Oncogenesis in Breast Cancer
Authors: Michael Baum
Journal: New England Journal of Medicine (2015)

Like other human anatomical systems, the mammary ducts and glands at the time of lactation adhere to a perfect fractal geometry - which is destroyed by breast cancer. Could a loss of fractal geometry of the blood supply to human tissue be an early step in oncogenesis?
Commentary: Screening for melanoma risk is misguided
Authors: D. Keeley
Journal: BMJ (1995)

With an incidence of malignant melanoma of 1 in 10000 a year1 2 a general practitioner with a registered list of 2000 patients will see about one new case every five years. Risk factors for melanoma have been identified, and one strategy for prevention is to target those at higher risk for more intensive advice on reducing their exposure to the sun and on what to do if moles change. This study investigates in an “affluent practice” some aspects of the feasibility of such a strategy. But is the strategy worth investigating at all? …
Tuberculosis treatment outcome in the European Union and European Economic Area: an analysis of surveillance data from 2002‒2011
Authors: Basel Karo, Barbara Hauer, Vahur Hollo, Marieke J. van der Werf, Lena Fiebig, Walter Haas
Journal: Eurosurveillance (2015)

Monitoring the treatment outcome (TO) of tuberculosis (TB) is essential to evaluate the effectiveness of the intervention and to identify potential barriers for TB control. The global target is to reach a treatment success rate (TSR) of at least 85%. We aimed to assess the TB TO in the European Union and European Economic Area (EU/EEA) between 2002 and 2011, and to identify factors associated with unsuccessful treatment. Only 18 countries reported information on TO for the whole observation period accounting for 250,854 new culture-confirmed pulmonary TB cases. The 85% target of TSR was not reached in any year between 2002 and 2011 and was on average 78%. The TSR for multidrug-resistant (MDR)-TB cases at 24-month follow-up was 49%. In the multivariable regression model, unsuccessful treatment was significantly associated with increasing age (odds ratio (OR) = 1.02 per a one-year increase, 95% confidence interval (CI): 1.02–1.02), MDR-TB (OR = 8.7, 95% CI: 5.09–14.97), male sex (OR = 1.40, 95% CI: 1.28–1.52), and foreign origin (OR = 1.32, 95% CI: 1.03–1.70). The data highlight that special efforts are required for patients with MDR-TB and the elderly aged ≥65 years, who have particularly low TSR. To allow for valid monitoring at EU level all countries should aim to report TO for all TB cases.
Reversal of P-glycoprotein-dependent resistance to adriamycin by 5-bromotetrandrine in K562/A02 cell line
Authors: B. Chen, J. Wang, C. Gao, J. Ding, Y. Sun, F. Gao, J. Cheng, G. Zhao, N. Chen
Journal: Journal of Clinical Oncology (2008)

13557 Background: Bromotetrandrine (BrTet), a bromized derivative of tetrandrine (Tet), could effectively reverse P-glycoprotein mediated multidrug resistance. The present study aimed to evaluate the MDR reversal activity of bromotetrandrine (BrTet), a bromized derivative of tetrandrine (Tet), in vitro. Methods: The inhibitory effects of adriamycin (ADM) used alone or in combination with BrTet or Tet on the proliferation of K562 and K562/A02 cells were evaluated by MTT assay. ADM accumulation and the protein levels of P- glycoprotein (P-gp) were analyzed by fluorospectrophotometry, respectively. The mRNA levels of P-gp were determined by RT-PCR. The in vivo effect of Tet was investigated using nude mice grafted with sensitive human leukemia cell line K562 and MDR cell line K562/A02. Results: BrTet at 0.25, 0.5 and 1μM reversed ADM resistance in MDR K562/A02 cells dose-dependently and its potency was greater than that of Tet at the same concentrations. Fluorospectrophotometric assay showed that BrTet significantly increased the intracellular accumulation of ADM in K562/A02 cells in a dose-dependent manner. BrTet also inhibited the overexpression of P-gp in K562/A02 cells, and had an effect of decrease on mdr1 expression. In nude mice bearing K562 xenografts on the left flank and K562/A02 xenografts on the right flank, i.p. injection of 10 mg/kg BrTet significantly enhanced the antitumor activity of ADM against K562/A02 xenografts with inhibitory rates of 26.1%, while ADM alone inhibited the growth of KBv200 xenografts by only 5.8%. No enhancement by BrTet was seen in K562 xenografts. Conclusions: BrTet showed significant MDR reversal activity in vitro and in vivo. Its activity may be related to the inhibition of P-gp overexpression and the increase in intracellular accumulation of anticancer drugs. BrTet may be a promising MDR modulator for eventual assessment in the clinic. No significant financial relationships to disclose.
European watchdog is failing to hold tobacco industry to account over smuggling
Authors: Martin McKee, Anna B Gilmore
Journal: BMJ (2015)

What are agreements with the industry worth?

For over a decade the European Union’s antifraud organisation, OLAF (Office Europeen de Lutte Antifraude) has, controversially, engaged with the tobacco industry, ostensibly to counter tobacco smuggling. This is despite extensive evidence of industry complicity in smuggling,1 a situation that seems to persist.2 It also represents a U-turn by OLAF, which in 2000 filed a lawsuit accusing tobacco manufacturers of “an ongoing global scheme to smuggle cigarettes.”

In 2004 OLAF halted this litigation in exchange for a legally binding agreement with Philip Morris International to tackle the illicit trade.3 Subsequently, the European Union signed similar agreements with three other big tobacco companies. The agreement with Philip Morris is about to expire, and talks on possible renewal have begun.

These agreements may have undermined OLAF’s judgment.3 Analysis has highlighted a lack of transparency in how the agreements operated, …
Overexpression of the Long Non-coding RNA SChLAP1 Independently Predicts Lethal Prostate Cancer
Authors: Rohit Mehra, Aaron M. Udager, Thomas U. Ahearn, Xuhong Cao, Felix Y. Feng, Massimo Loda, Joshua S. Petimar, Philip Kantoff, Lorelei A. Mucci, Arul M. Chinnaiyan
Journal: European Urology (2015)
Personalized Preclinical Trials in BRAF Inhibitor–Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies
Authors: Clemens Krepler, Min Xiao, Katrin Sproesser, Patricia A. Brafford, Batool Shannan, Marilda Beqiri, Qin Liu, Wei Xu, Bradley Garman, Katherine L. Nathanson, Xiaowei Xu, Giorgos C. Karakousis, Gordon B. Mills, Yiling Lu, Tamer A. Ahmed, Poulikos I. Poulikakos, Giordano Caponigro, Markus Boehm, Malte Peters, Lynn M. Schuchter, Ashani T. Weeraratna, Meenhard Herlyn
Journal: Clinical Cancer Research (2015)

To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models.We established 12 PDXs from BRAF inhibitor-progressed melanoma patients. Following expansion, PDXs were analyzed using targeted sequencing and reverse-phase protein arrays. By using multi-arm preclinical trial designs, we identified efficacious precision medicine approaches.We identified alterations previously described as drivers of resistance: NRAS mutations in 3 PDXs, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and aberrant PTEN in 7. At the protein level, re-activation of phospho-MAPK predominated, with parallel activation of PI3K in a subset. Second-line efficacy of the pan-PI3K inhibitor BKM120 with either BRAF (encorafenib)/MEK (binimetinib) inhibitor combination or the ERK inhibitor VX-11e was confirmed in vivo Amplification of MET was observed in 3 PDX models, a higher frequency than expected and a possible novel mechanism of resistance. Importantly, MET amplification alone did not predict sensitivity to the MET inhibitor capmatinib. In contrast, capmatinib as single agent resulted in significant but transient tumor regression in a PDX with resistance to BRAF/MEK combination therapy and high pMET. The triple combination capmatinib/encorafenib/binimetinib resulted in complete and sustained tumor regression in all animals.Genomic and proteomic data integration identifies dual-core pathway inhibition as well as MET as combinatorial targets. These studies provide evidence for biomarker development to appropriately select personalized therapies of patients and avoid treatment failures. See related commentary by Hartsough and Aplin, p. 1550.