Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.

Research Event

Current therapeutic strategies for diabetic foot ulcer (DFU) have focused on developing topical healing agents, but few agents have controlled prospective data to support their effectiveness in promoting wound healing. We tested a stem cell mobilizing therapy for DFU using a combination of AMD3100 and low-dose FK506 (tacrolimus) (AF) in streptozocin-induced type 1 diabetic (T1DM) rats and type 2 diabetic Goto-Kakizaki (GK) rats that had developed peripheral artery disease and neuropathy. Here, we show that the time for healing back wounds in T1DM rats was reduced from 27 to 19 days, and the foot wound healing time was reduced from 25 to 20 days by treatment with AF (subcutaneously, every other day). Similarly, in GK rats treated with AF, the healing time on back wounds was reduced from 26 to 21 days. Further, this shortened healing time was accompanied by reduced scar and by regeneration of hair follicles. We found that AF therapy mobilized and recruited bone marrow–derived CD133⁺ and CD34⁺ endothelial progenitor cells and Ym1/2⁺ M2 macrophages into the wound sites, associated with enhanced capillary and hair follicle neogenesis. Moreover, AF therapy improved microcirculation in diabetic and neuropathic feet in GK rats. This study provides a novel systemic therapy for healing DFU.

¹⁶⁶Ho-microspheres have recently been approved for clinical use for hepatic radioembolization in the European Union. The aim of this study was to investigate the absorbed dose–response relationship and its association with overall survival for ¹⁶⁶Ho radioembolization in patients with liver metastases. Methods: Patients treated in the HEPAR I and II studies who underwent an ¹⁸F-FDG PET/CT scan at baseline, a posttreatment ¹⁶⁶Ho SPECT/CT scan, and another ¹⁸F-FDG PET/CT scan at the 3-mo follow-up were included for analysis. The posttreatment ¹⁶⁶Ho-microsphere activity distributions were estimated with quantitative SPECT/CT reconstructions using a quantitative Monte Carlo–based method. The response of each tumor was based on the change in total lesion glycolysis (TLG) between baseline and follow-up and was placed into 1 of 4 categories, according to the PERCIST criteria, ranging from complete response to progressive disease. Patient-level response was grouped according to the average change in TLG per patient. The absorbed dose–response relationship was assessed using a linear mixed model to account for correlation of tumors within patients. Median overall survival was compared between patients with and without a metabolic liver response, using a log-rank test. Results: Thirty-six patients with a total of 98 tumors were included. The relation between tumor-absorbed dose and both tumor-level and patient-level response was explored. At a tumor level, a significant difference in geometric mean absorbed dose was found between complete response (232 Gy; 95% confidence interval [CI], 178–303 Gy; n = 32) and stable disease (147 Gy; 95% CI, 113–191 Gy; n = 28) (P = 0.01) and between complete response and progressive disease (117 Gy; 95% CI, 87–159 Gy; n = 21) (P = 0.0008). This constitutes a robust absorbed dose–response relationship. At a patient level, a significant difference was found between patients with complete or partial response (210 Gy; 95% CI, 161–274 Gy; n = 13) and patients with progressive disease (116 Gy; 95% CI, 81–165 Gy; n = 9) (P = 0.01). Patients were subsequently grouped according to their average change in TLG. Patients with an objective response (complete or partial) exhibited a significantly higher overall survival than nonresponding patients (stable or progressive disease) (median, 19 mo vs. 7.5 mo; log-rank, P = 0.01). Conclusion: These results confirm a significant absorbed dose–response relationship in ¹⁶⁶Ho radioembolization. Treatment response is associated with a higher overall survival.

We aimed to assess the value of ¹¹C-choline PET in patients with primary hyperparathyroidism and negative or discordant results on ^99mTc-sestamibi imaging and neck ultrasound. Methods: Eighty-seven such patients were assessed and subsequently underwent parathyroidectomy. PET/CT image data were analyzed semiquantitatively using SUV_max and SUV ratios (target to contralateral thyroid gland and carotid artery). A positive PET/CT result was defined as focal uptake significantly higher than regular thyroid tissue. Ectopic foci were also considered positive. Inconclusive PET/CT cases were defined as a lesion with uptake equal to normal thyroid tissue. If no prominent or ectopic uptake was detectable, the PET/CT result was considered negative. Results: When dichotomizing the ¹¹C-choline PET/CT imaging results by defining lesions with both positive and inconclusive uptake as positive, we found 84 of 92 lesions (91.3%) to have true-positive uptake whereas 8 lesions (8.7%) had false-positive uptake. One lesion showed false-negative uptake; the sensitivity was 98.8%. The corresponding positive predictive value for lesions was 91.3%. The mean SUV_max was 6.15 ± 4.92 in 72 lesions with positive uptake (70 patients) and 2.96 ± 2.32 in 20 lesions with inconclusive uptake (18 patients). Conclusion: These results in a large group of patients indicate that ¹¹C-choline PET/CT is a promising tool for parathyroid adenoma localization when ultrasound and ^99mTc-sestamibi imaging yield negative or discordant results.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, definitive treatment usually requiring surgical removal of the offending parathyroid glands. To perform focused surgical approaches, it is necessary to localize all hyperfunctioning glands. The aim of the study was to compare the efficiency of established conventional scintigraphic imaging modalities with emerging ¹⁸F-fluorocholine PET/CT imaging in preoperative localization of hyperfunctioning parathyroid glands in a larger series of PHPT patients. Methods: In total, 103 patients with PHPT were imaged preoperatively with ¹⁸F-fluorocholine PET/CT and conventional scintigraphic imaging methods, consisting of ^99mTc-sestamibi SPECT/CT, ^99mTc-sestamibi/pertechnetate subtraction imaging, and ^99mTc-sestamibi dual-phase imaging. The results of histologic analysis, as well as intact parathyroid hormone and serum calcium values obtained 1 d after surgery and on follow-up, served as the standard of truth for evaluation of imaging results. Results: Diagnostic performance of ¹⁸F-fluorocholine PET/CT surpassed conventional scintigraphic methods (separately or combined), with calculated sensitivity of 92% for PET/CT and 39%–56% for conventional imaging (65% for conventional methods combined) in the entire patient group. Subgroup analysis, differentiating single and multiple hyperfunctioning parathyroid glands, showed PET/CT to be most valuable in the group with multiple hyperfunctioning glands, with sensitivity of 88%, whereas conventional imaging was significantly inferior, with sensitivity of 22%–34% (44% combined). Conclusion: ¹⁸F-fluorocholine PET/CT is a diagnostic modality superior to conventional imaging methods in patients with PHPT, allowing for accurate preoperative localization.

¹⁸F-DCFPyL (2-(3-{1-carboxy-5-[(6-¹⁸F-fluoropyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) is a promising PET radiopharmaceutical targeting prostate-specific membrane antigen (PSMA). We present our experience with this single-academic-center prospective study evaluating the positivity rate of ¹⁸F-DCFPyL PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC). Methods: We prospectively enrolled 72 men (52–91 y old; mean ± SD, 71.5 ± 7.2) with BCR after primary definitive treatment with prostatectomy (n = 42) or radiotherapy (n = 30). The presence of lesions compatible with PC was evaluated by 2 independent readers. Fifty-nine patients had scans concurrent with at least one other conventional scan: bone scanning (24), CT (21), MR (20), ¹⁸F-fluciclovine PET/CT (18), or ¹⁸F-NaF PET (14). Findings from ¹⁸F-DCFPyL PET/CT were compared with those from other modalities. Impact on patient management based on ¹⁸F-DCFPyL PET/CT was recorded from clinical chart review. Results: ¹⁸F-DCFPyL PET/CT had an overall positivity rate of 85%, which increased with higher prostate-specific antigen (PSA) levels (ng/mL): 50% (PSA < 0.5), 69% (0.5 ≤ PSA < 1), 100% (1 ≤ PSA < 2), 91% (2 ≤ PSA < 5), and 96% (PSA ≥ 5). ¹⁸F-DCFPyL PET detected more lesions than conventional imaging. For anatomic imaging, 20 of 41 (49%) CT or MRI scans had findings congruent with ¹⁸F-DCFPyL, whereas ¹⁸F-DCFPyL PET was positive in 17 of 41 (41%) cases with negative CT or MRI findings. For bone imaging, 26 of 38 (68%) bone or ¹⁸F-NaF PET scans were congruent with ¹⁸F-DCFPyL PET, whereas ¹⁸F-DCFPyL PET localized bone lesions in 8 of 38 (21%) patients with negative results on bone or ¹⁸F-NaF PET scans. In 8 of 18 (44%) patients, ¹⁸F-fluciclovine PET had located the same lesions as did ¹⁸F-DCFPyL PET, whereas 5 of 18 (28%) patients with negative ¹⁸F-fluciclovine findings had positive ¹⁸F-DCFPyL PET findings and 1 of 18 (6%) patients with negative ¹⁸F-DCFPyL findings had uptake in the prostate bed on ¹⁸F-fluciclovine PET. In the remaining 4 of 18 (22%) patients, ¹⁸F-DCFPyL and ¹⁸F-fluciclovine scans showed different lesions. Lastly, 43 of 72 (60%) patients had treatment changes after ¹⁸F-DCFPyL PET and, most noticeably, 17 of these patients (24% total) had lesion localization only on ¹⁸F-DCFPyL PET, despite negative results on conventional imaging. Conclusion: ¹⁸F-DCFPyL PET/CT is a promising diagnostic tool in the work-up of biochemically recurrent PC, given the high positivity rate as compared with Food and Drug Administration–approved currently available imaging modalities and its impact on clinical management in 60% of patients.

OBJECTIVE

Self-management education and support are essential for improved diabetes control. A 1-year randomized telephonic diabetes self-management intervention (Bronx A1C) among a predominantly Latino and African American population in New York City was found effective in improving blood glucose control. To further those findings, this current study assessed the intervention’s impact in reducing health care utilization and costs over 4 years.

Kasia J. Lipska
Apr 1, 2017; 40:468-475
Emerging Science and Concepts for Management of Diabetes and Aging

Frank B. Hu
Jun 1, 2011; 34:1249-1257
Kelly West Award Lecture

Frank B. Hu
Jun 1, 2011; 34:1249-1257
Kelly West Award Lecture

OBJECTIVE

To assess functional β-cell capacity in type 2 diabetes during 2 years of remission induced by dietary weight loss.

Nearly 22 million immigrants—about half of the overall immigrant population—were naturalized U.S. citizens in fiscal year 2017. In the same year, more than 707,000 immigrants became U.S. citizens. Naturalized citizens tend to have higher incomes and educational attainment compared to other immigrants, as this data-rich article explores.

OBJECTIVE

To compare the risk of lactic acidosis hospitalization between patients treated with metformin versus sulfonylureas following development of reduced kidney function.

2017 saw the introduction of several bills—two of them by Senate Republicans in the weeks following the Trump administration’s announcement that it would terminate the Deferred Action for Childhood Arrivals (DACA) program—that would provide a pathway to conditional and then legal permanent residence to unauthorized immigrants brought to the United States as children, if they meet a range of educational, professional, and other criteria.

Historian Elizabeth Stordeur Pryor leads a thoughtful and history-backed examination of one of the most divisive words in the English language: the N-word. Drawing from personal experience, she explains how reflecting on our points of encounter with the word can help promote productive discussions and, ultimately, create a framework that reshapes education around the complicated history of racism in the US.

If you're feeling anxious or fearful during the coronavirus pandemic, you're not alone. Offering hope and understanding, author Elizabeth Gilbert reflects on how to stay present, accept grief when it comes and trust in the strength of the human spirit. "Resilience is our shared genetic inheritance," she says. (This virtual conversation is part of the TED Connects series, hosted by head of TED Chris Anderson and head of curation Helen Walters. Recorded April 2, 2020)

Recounting her story of finding opportunity and stability in the US, Elizabeth Camarillo Gutierrez examines the flaws in narratives that simplify and idealize the immigrant experience -- and shares hard-earned wisdom on the best way to help those around us. "Our world is one that flourishes when different voices come together," she says.

Told from two points of view: Drake: Most guys like their dads. Most guys aren't the son of the literal devil. When Daddy Dearest tells me its unseemly for the last living son of the Lord of Hell to be unmarried, I hate to think who he has in mind. Until, I remember I'm technically already married. Yeah, she's human and I was all of eight at the time. But, still counts. Now I just need to get my wife to Hell for a meet and greet with Pops and send her back home. Except, our marriage won't technically be legit until it's consummated. And I don't know that I want to send her home... Wren: Most girls live normal lives. Most girls aren't married to the devil's son. There is something weirdly familiar about the new guy next door, but I can't place it. Then a weird little demon thing turns up in my room to tell me a prince of Hell wishes for an audience with me. Oh, yeah. And, apparently - while I'm not even eighteen yet - he's my husband? So, I find myself stuck in Hell with a husband. And, I guess I don't hate it as much as I thought I would. There's always something going on and things to discover. And soon, I don't know that I want to go home.

Elizabeth I, Queen of England, 1533-1603 -- Sexual behavior.

Stone, E. Constance (Emma Constance), 1856-1902.

Information visualization.

Women immigrants -- Australia -- History.

Thornley, Anastasia.

Marshall, John, 1787-1861.

Meat industry and trade -- Environmental aspects.

Illumination of books and manuscripts, Medieval -- Themes, motives -- Exhibitions.

London : Macmillan, 1870.

Valencia : M. Alufre, 1886.

London : Longmans, Green, Reader and Dyer, 1870.

London : [Published not identified], 1871.

London : [Published not identified], 1872.

London : [Published not identified], 1873.

London : [Published not identified], 1874.

London : [Published not identified], 1875.

London : [Published not identified], 1876.

[London] : [Published not identified], [1877]

Rockville, Maryland : National Institute on Drug Abuse, 1988.

Rockville, Maryland : National Institute on Drug Abuse, 1986.

Daren Wang, Yi Yu, Alessandro Rinaldo.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1917--1961.

Abstract:
The problem of univariate mean change point detection and localization based on a sequence of $n$ independent observations with piecewise constant means has been intensively studied for more than half century, and serves as a blueprint for change point problems in more complex settings. We provide a complete characterization of this classical problem in a general framework in which the upper bound $sigma ^{2}$ on the noise variance, the minimal spacing $Delta $ between two consecutive change points and the minimal magnitude $kappa $ of the changes, are allowed to vary with $n$. We first show that consistent localization of the change points is impossible in the low signal-to-noise ratio regime $frac{kappa sqrt{Delta }}{sigma }preceq sqrt{log (n)}$. In contrast, when $frac{kappa sqrt{Delta }}{sigma }$ diverges with $n$ at the rate of at least $sqrt{log (n)}$, we demonstrate that two computationally-efficient change point estimators, one based on the solution to an $ell _{0}$-penalized least squares problem and the other on the popular wild binary segmentation algorithm, are both consistent and achieve a localization rate of the order $frac{sigma ^{2}}{kappa ^{2}}log (n)$. We further show that such rate is minimax optimal, up to a $log (n)$ term.

We focus on estimating emph{a priori} generalization error of two-layer ReLU neural networks (NNs) trained by mean squared error, which only depends on initial parameters and the target function, through the following research line. We first estimate emph{a priori} generalization error of finite-width two-layer ReLU NN with constraint of minimal norm solution, which is proved by cite{zhang2019type} to be an equivalent solution of a linearized (w.r.t. parameter) finite-width two-layer NN. As the width goes to infinity, the linearized NN converges to the NN in Neural Tangent Kernel (NTK) regime citep{jacot2018neural}. Thus, we can derive the emph{a priori} generalization error of two-layer ReLU NN in NTK regime. The distance between NN in a NTK regime and a finite-width NN with gradient training is estimated by cite{arora2019exact}. Based on the results in cite{arora2019exact}, our work proves an emph{a priori} generalization error bound of two-layer ReLU NNs. This estimate uses the intrinsic implicit bias of the minimum norm solution without requiring extra regularity in the loss function. This emph{a priori} estimate also implies that NN does not suffer from curse of dimensionality, and a small generalization error can be achieved without requiring exponentially large number of neurons. In addition the research line proposed in this paper can also be used to study other properties of the finite-width network, such as the posterior generalization error.

Boosting is one of the most successful ideas in machine learning. The most well-accepted explanations for the low generalization error of boosting algorithms such as AdaBoost stem from margin theory. The study of margins in the context of boosting algorithms was initiated by Schapire, Freund, Bartlett and Lee (1998) and has inspired numerous boosting algorithms and generalization bounds. To date, the strongest known generalization (upper bound) is the $k$th margin bound of Gao and Zhou (2013). Despite the numerous generalization upper bounds that have been proved over the last two decades, nothing is known about the tightness of these bounds. In this paper, we give the first margin-based lower bounds on the generalization error of boosted classifiers. Our lower bounds nearly match the $k$th margin bound and thus almost settle the generalization performance of boosted classifiers in terms of margins.

Trang Quynh Nguyen, Elizabeth A. Stuart.

Source: The Annals of Applied Statistics, Volume 14, Number 1, 518--520.