Publications by authors named "Michael G Kauffman"

10 Publications

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Effect of Age and Frailty on the Efficacy and Tolerability of Once-Weekly Selinexor, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma.

Am J Hematol 2021 Mar 23. Epub 2021 Mar 23.

Medical University of Silesian, Katowice, Poland.

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analyses of the multicenter, prospective, randomised BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, P=0.024), ≥VGPR (OR, 1.68, P=0.027), PFS (HR 0.55, P=0.002), and improved OS (HR 0.63, P=0.030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, P=0.08) and OS (HR 0.62, P=0.062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had lower incidence of grade ≥2 peripheral neuropathy in ≥65 (22% vs 37%; P=0.0060) and frail patients (15% vs 44%; P=0.0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ajh.26172DOI Listing
March 2021

Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial.

Lancet 2020 11;396(10262):1563-1573

General Hospital Evangelismos, Athens, Greece.

Background: Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma.

Methods: This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020.

Findings: Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died.

Interpretation: A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy.

Funding: Karyopharm Therapeutics.
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http://dx.doi.org/10.1016/S0140-6736(20)32292-3DOI Listing
November 2020

Integrated safety profile of selinexor in multiple myeloma: experience from 437 patients enrolled in clinical trials.

Leukemia 2020 09 24;34(9):2430-2440. Epub 2020 Feb 24.

Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Selinexor is an oral, small molecule inhibitor of the nuclear export protein exportin 1 with demonstrated activity in hematologic and solid malignancies. Side effects associated with selinexor include nausea, vomiting, fatigue, diarrhea, decreased appetite, weight loss, thrombocytopenia, neutropenia, and hyponatremia. We reviewed 437 patients with multiple myeloma treated with selinexor and assessed the kinetics of adverse events and impact of supportive care measures. Selinexor reduced both platelets and neutrophils over the first cycle of treatment and reached a nadir between 28 and 42 days. Platelet transfusions and thrombopoietin receptor agonists were effective at treating thrombocytopenia, and granulocyte colony stimulating factors were effective at resolving neutropenia. The onset of gastrointestinal side effects (nausea, vomiting, and diarrhea) was most common during the first 1-2 weeks of treatment. Nausea could be mitigated with 5-HT3 antagonists and either neurokinin 1 receptor antagonists, olanzapine, or cannbainoids. Loperamide and bismuth subsalicylate ameliorated diarrhea. The primary constitutional side effects of fatigue and decreased appetite could be managed with methylphenidate, megestrol, cannabinoids or olanzapine, respectively. Hyponatremia was highly responsive to sodium replacement. Selinexor has well-established adverse effects that mainly occur within the first 8 weeks of treatment, are reversible, and respond to supportive care.
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http://dx.doi.org/10.1038/s41375-020-0756-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449872PMC
September 2020

Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.

N Engl J Med 2019 08;381(8):727-738

From the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai (A.C., S.P., S.J.), and New York University Langone Medical Center (D.K.) - both in New York; the Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.T.V.); the School of Medicine, National and Kapodistrian University of Athens, Athens (M.G., M. Dimopoulos); the Winship Cancer Institute, Emory University, Atlanta (A.K.N., S.L.); Massachusetts General Hospital Cancer Center (A.J.Y.), Tufts Medical Center (R.L.C.), and the Dana-Farber Cancer Institute (P.G.R.), Boston, and Karyopharm Therapeutics, Newton (M.G.K., S.S., L.L., S. Tang, C.P., J.-R.S.-M., M.C., H.C., Y.L., J.S.) - all in Massachusetts; Johns Hopkins University, Baltimore (C.A.H.); the University of Nantes, Nantes (P.M.), Hôpital Necker (L.F.), Hôpital Saint-Antoine (M.M.), and La Pitié-Salpêtrière Hospital (S.C.), Paris, University Hospital, Lille (T.F.), Centre Hospitalier Lyon Sud, Pierre-Benite (L.K.), and Centre Hospitalo-Universitaire Vandoeuvre-lès-Nancy, Nancy (A.P.) - all in France; the Mayo Clinic, Rochester, MN (D.D.); the University of Michigan, Ann Arbor (C.C.); the Mayo Clinic of Arizona, Phoenix (A.K.S.); Hackensack University Medical Center, Hackensack, NJ (J.R.); Washington University School of Medicine, St. Louis (R.V.); Lineberger Comprehensive Cancer Center at University of North Carolina-Chapel Hill, Chapel Hill (S. Tuchman); the University of Heidelberg, Heidelberg (M.S.R.), University Medical Center Hamburg-Eppendorf, Hamburg (K.C.W.), the University of Tübingen, Tübingen (K.C.W.), University Hospital Würzburg, Würzburg (M.S.), the University of Freiburg, Freiburg (M.E.), and Gemeinschaftspraxis Hämatologie-Onkologie, Dresden (T.I.) - all in Germany; the University of Leuven, Leuven (M. Delforge), Institut Jules Bordet, Université Libre de Bruxelles, Brussels (N.M.), University Hospital Ghent, Ghent (P.V.), and Centre Hospitalier Universitaire Université Catholique de Louvain Namur, Yvoir (C.D.) - all in Belgium; Vanderbilt University Medical Center, Nashville (R.F.C.); Sylvester Cancer Center, University of Miami, Miami (J.E.H.); the University of Alabama at Birmingham, Birmingham (L.J.C.); Yale School of Medicine, New Haven, CT (T.L.P.); Baylor University Medical Center, Dallas (M.L.); the David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (G.S.); and University Hospital Krems, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria (K.P.).

Background: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.

Methods: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.

Results: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.

Conclusions: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).
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http://dx.doi.org/10.1056/NEJMoa1903455DOI Listing
August 2019

Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration.

Oncotarget 2017 Oct 17;8(47):82144-82155. Epub 2017 Jul 17.

Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States with a majority of these patients dying from aggressively invasive and metastatic disease. There is growing evidence that suggests an important role for microRNAs (miRNAs) in the pathobiology of aggressive PDAC. In this study, we found that the expression of miR-145 was significantly lower in PDAC cells when compared to normal pancreatic duct epithelial cells. Here we show that inhibition of the nuclear exporter protein exportin 1 (XPO1; also known as chromosome maintenance region 1 [CRM1]) by siRNA knockdown or by the Selective Inhibitor of Nuclear Export (SINE) compound (KPT-330; selinexor) increases miR-145 expression in PDAC cells resulting in the decreased cell proliferation and migration capacities. A similar result was obtained with forced expression of miR-145 in PDAC cells. To this end, SINE compound treatment mediated the down-regulation of known miR-145 targets genes including EGFR, MMP1, MT-MMP, c-Myc, Pak4 and Sox-2. In addition, selinexor induced the expression of two important tumor suppressive miRNAs miR-34c and let-7d leading to the up-regulation of p21. These results are the first to report that targeted inhibition of the nuclear export machinery could restore tumor suppressive miRNAs in PDAC that warrants further clinical investigations.
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http://dx.doi.org/10.18632/oncotarget.19285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669877PMC
October 2017

XPO1 Inhibition Preferentially Disrupts the 3D Nuclear Organization of Telomeres in Tumor Cells.

J Cell Physiol 2016 12 8;231(12):2711-9. Epub 2016 Apr 8.

Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.

Previous work has shown that the three-dimensional (3D) nuclear organization of telomeres is altered in cancer cells and the degree of alterations coincides with aggressiveness of disease. Nuclear pores are essential for spatial genome organization and gene regulation and XPO1 (exportin 1/CRM1) is the key nuclear export protein. The Selective Inhibitor of Nuclear Export (SINE) compounds developed by Karyopharm Therapeutics (KPT-185, KPT-330/selinexor, and KPT-8602) inhibit XPO1 nuclear export function. In this study, we investigated whether XPO1 inhibition has downstream effects on the 3D nuclear organization of the genome. This was assessed by measuring the 3D telomeric architecture of normal and tumor cells in vitro and ex vivo. Our data demonstrate for the first time a rapid and preferential disruption of the 3D nuclear organization of telomeres in tumor cell lines and in primary cells ex vivo derived from treatment-naïve newly diagnosed multiple myeloma patients. Normal primary cells in culture as well as healthy lymphocyte control cells from the same patients were minimally affected. Using both lymphoid and non-lymphoid tumor cell lines, we found that the downstream effects on the 3D nuclear telomere structure are independent of tumor type. We conclude that the 3D nuclear organization of telomeres is a sensitive indicator of cellular response when treated with XPO1 inhibitors. J. Cell. Physiol. 231: 2711-2719, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcp.25378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111786PMC
December 2016

Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin.

Oncotarget 2015 May;6(15):13119-32

Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Survivin, which is highly expressed and promotes cell survival in diffuse malignant peritoneal mesothelioma (DMPM), exclusively relies on exportin 1 (XPO1/CRM1) to be shuttled into the cytoplasm and perform its anti-apoptotic function. Here, we explored the efficacy of Selective Inhibitors of Nuclear Export (SINE), KPT-251, KPT-276 and the orally available, clinical stage KPT-330 (selinexor), in DMPM preclinical models. Exposure to SINE induced dose-dependent inhibition of cell growth, cell cycle arrest at G1-phase and caspase-dependent apoptosis, which were consequent to a decrease of XPO1/CRM1 protein levels and the concomitant nuclear accumulation of its cargo proteins p53 and CDKN1a. Cell exposure to SINE led to a time-dependent reduction of cytoplasmic survivin levels. In addition, after an initial accumulation, the nuclear protein abundance progressively decreased, as a consequence of an enhanced ubiquitination and proteasome-dependent degradation. SINE and the survivin inhibitor YM155 synergistically cooperated in reducing DMPM cell proliferation. Most importantly, orally administered SINE caused a significant anti-tumor effect in subcutaneous and orthotopic DMPM xenografts without appreciable toxicity. Overall, we have demonstrated a marked efficacy of SINE in DMPM preclinical models that may relay on the interference with survivin intracellular distribution and function. Our study suggests SINE-mediated XPO1/CRM1 inhibition as a novel therapeutic option for DMPM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537003PMC
http://dx.doi.org/10.18632/oncotarget.3761DOI Listing
May 2015

Biologic activity of the novel orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 against canine melanoma cell lines.

BMC Vet Res 2014 Jul 15;10:160. Epub 2014 Jul 15.

Departments of Veterinary Biosciences and Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd,, Columbus, OH 43210, USA.

Background: Exportin 1 (XPO1, also known as CRM1), is a chaperone protein responsible for the export of over 200 target proteins out of the nucleus. The expression and activity of XPO1 is upregulated in several human cancers and its expression is also linked to the development of chemotherapy resistance. Recent studies using both human and murine cancer cell lines have demonstrated that XPO1 is a relevant target for therapeutic intervention. The present study sought to characterize the biologic activity of an orally bioavailable selective inhibitor of nuclear export (SINE), KPT-335, against canine melanoma cell lines as a prelude to future clinical trials in dogs with melanoma.

Results: We evaluated the effects of KPT-335 on 4 canine malignant melanoma cell lines and found that KPT-335 inhibited proliferation, blocked colony formation, and induced apoptosis of treated cells at biologically relevant concentrations of drug. Additionally, KPT-335 downregulated XPO1 protein while inducing a concomitant increase in XPO1 messenger RNA. Lastly, KPT-335 treatment of cell lines upregulated the expression of both protein and mRNA for the tumor suppressor proteins p53 and p21, and promoted their nuclear localization.

Conclusions: KPT-335 demonstrates biologic activity against canine melanoma cell lines at physiologically relevant doses, suggesting that KPT-335 may represent a viable treatment option for dogs with malignant melanoma.
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http://dx.doi.org/10.1186/1746-6148-10-160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105800PMC
July 2014

XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple-negative breast cancer.

Mol Cancer Ther 2014 Mar 15;13(3):675-86. Epub 2014 Jan 15.

Corresponding Author: Rachel A. Altura, Department of Pediatrics, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903.

Inhibition of XPO1 (CRM1)-mediated nuclear export of multiple tumor suppressor proteins has been proposed as a novel cancer therapeutic strategy to turn off oncogenic signals and enhance tumor suppression. Survivin is a multifunctional protein with oncogenic properties when expressed in the cytoplasm that requires the XPO1-RanGTP complex for its nuclear export. We investigated the antitumor mechanisms of the drug-like selective inhibitors of nuclear export (SINE) XPO1 antagonists KPT-185, KPT-251 KPT-276, and KPT-330 in estrogen receptor-positive and triple-negative breast cancer (TNBC) cell lines and xenograft models of human breast tumors. KPT compounds significantly inhibited breast cancer cell growth and induced tumor cell death, both in vitro and in vivo. These drugs initially promoted survivin accumulation within tumor cell nuclei. However, their major in vitro effect was to decrease survivin cytoplasmic protein levels, correlating with the onset of apoptosis. XPO1 inhibition repressed Survivin transcription by inhibiting CREB-binding protein-mediated STAT3 acetylation, and blocking STAT3 binding to the Survivin promoter. In addition, caspase-3 was activated to cleave survivin, rendering it unavailable to bind X-linked inhibitor of apoptosis protein and block the caspase cascade. Collectively, these data demonstrate that XPO1 inhibition by SINE compounds represses STAT3 transactivation to block the selective oncogenic properties of survivin and supports their clinical use in TNBC.
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http://dx.doi.org/10.1158/1535-7163.MCT-13-0416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954411PMC
March 2014

Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias.

Blood 2013 Oct 22;122(17):3034-44. Epub 2013 Aug 22.

Human Cancer Genetics Program, Department Molecular Virology Immunology and Medical Genetics.

As tyrosine kinase inhibitors (TKIs) fail to induce long-term response in blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL), novel therapies targeting leukemia-dysregulated pathways are necessary. Exportin-1 (XPO1), also known as chromosome maintenance protein 1, regulates cell growth and differentiation by controlling the nucleocytoplasmic trafficking of proteins and RNAs, some of which are aberrantly modulated in BCR-ABL1(+) leukemias. Using CD34(+) progenitors from CML, B-ALL, and healthy individuals, we found that XPO1 expression was markedly increased, mostly in a TKI-sensitive manner, in CML-BC and Ph(+) B-ALL. Notably, XPO1 was also elevated in Ph(-) B-ALL. Moreover, the clinically relevant XPO1 inhibitor KPT-330 strongly triggered apoptosis and impaired the clonogenic potential of leukemic, but not normal, CD34(+) progenitors, and increased survival of BCR-ABL1(+) mice, 50% of which remained alive and, mostly, became BCR-ABL1 negative. Moreover, KPT-330 compassionate use in a patient with TKI-resistant CML undergoing disease progression significantly reduced white blood cell count, blast cells, splenomegaly, lactate dehydrogenase levels, and bone pain. Mechanistically, KPT-330 altered the subcellular localization of leukemia-regulated factors including RNA-binding heterogeneous nuclear ribonucleoprotein A1 and the oncogene SET, thereby inducing reactivation of protein phosphatase 2A tumor suppressor and inhibition of BCR-ABL1 in CML-BC cells. Because XPO1 is important for leukemic cell survival, KPT-330 may represent an alternative therapy for TKI-refractory Ph(+) leukemias.
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http://dx.doi.org/10.1182/blood-2013-04-495374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811176PMC
October 2013