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.

Barbara H. Braffett
May 1, 2020; 69:1000-1010
Complications

In this first episode of a three-part series on “Disrupting Therapeutic Inertia in Diabetes Management,” Drs. John Russell and Neil Skolnik examine a case study of a 55-year-old man with type 2 diabetes (3 years duration, A1C 8.2%). In so doing, they review six articles that define achievement gaps in reaching A1C goals and the reasons for why those gaps exist. In episodes 2 and 3 of this series, Drs. Russell and Skolnik we will look at additional causes of therapeutic inertia and solutions for overcoming it. This special three-part series on therapeutic inertia is supported by independent educational grant from Sanofi (https://www.sanofi.com).

This issue will review:

1. Achievement of target therapeutic goals in persons with T2DM
2. Achievement of therapeutic goals from 2005 – 2015
3. Clinical Inertia in Newly Diagnosed Type 2 DM
4. Clinical Inertia over Time in Type 2 DM
5. Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use
6. Difference between Clinical Trial and Real-World Studies Achievement of Target A1C <7.0% in Patients Treated with Basal Insulin in RCTs and Clinical Practice

For more information about each of ADA’s science and medical journals, please visit www.diabetesjournals.org.

Presented by:

Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health

John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health

Lily was diagnosed at 14 years old with stage four Hodgkin's lymphoma and received six rounds of chemotherapy and two weeks of radiotherapy. She survived but now lives with the long term effects of that therapy - and joins us to discuss how it has impacted her quality of life. We're also joined by Saif Ahmad and Thankamma Ajithkumar, oncologists...

Sue Farrington is chair of the Patient Information Forum, a member organisation which promotes best practice in anyone who produces information for patients. In this podcast, she discusses what makes good patient information, why doctors should be pleased when patients arrive at an appointment with a long list of questions, and why patients are...

U.K. Prospective Diabetes Study Group
Nov 1, 1995; 44:1249-1258
Perspectives in Diabetes

Schwann cell–derived exosomes communicate with dorsal root ganglia (DRG) neurons. The current study investigated the therapeutic effect of exosomes derived from healthy Schwann cells (SC-Exos) on diabetic peripheral neuropathy (DPN). We found that intravenous administration of SC-Exos to type 2 diabetic db/db mice with peripheral neuropathy remarkably ameliorated DPN by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. These functional improvements were associated with the augmentation of epidermal nerve fibers and remyelination of sciatic nerves. Quantitative RT-PCR and Western blot analysis of sciatic nerve tissues showed that SC-Exo treatment reversed diabetes-reduced mature form of miRNA (miR)-21, -27a, and -146a and diabetes-increased semaphorin 6A (SEMA6A); Ras homolog gene family, member A (RhoA); phosphatase and tensin homolog (PTEN); and nuclear factor-B (NF-B). In vitro data showed that SC-Exos promoted neurite outgrowth of diabetic DRG neurons and migration of Schwann cells challenged by high glucose. Collectively, these novel data provide evidence that SC-Exos have a therapeutic effect on DPN in mice and suggest that SC-Exo modulation of miRs contributes to this therapy.

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110 activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110 inactivation was found to attenuate pathological retinal angiogenesis. p110 inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110 constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, ⁶⁴Cu (half-life, 12.7 h) and ²²⁵Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of ⁶⁴Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of ⁶⁸Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, ²²⁵Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of ⁶⁴Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of ⁶⁴Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for ⁶⁴Cu-FAPI-04 than for ⁶⁸Ga-FAPI-04, except in the heart, and excretion in the urine was higher for ⁶⁸Ga-FAPI-04 than for ⁶⁴Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. ²²⁵Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that ⁶⁴Cu-FAPI-04 and ²²⁵Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog ¹⁷⁷Lu-DOTA-(d-Glu)₆-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH₂ (¹⁷⁷Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (~80 μg) of ¹⁷⁷Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of ¹⁷⁷Lu-PP-F11N to assess safety. Results: In all patients, ¹⁷⁷Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85–1.04), 0.42 (IQR: 0.25–1.01), 0.11 (IQR: 0.07–0.13), and 0.028 (IQR: 0.026–0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11–14.4) without SG and 13.0 (IQR: 10.2–18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14–4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: ¹⁷⁷Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, ¹⁷⁷Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of ¹⁷⁷Lu-PP-F11N.

OBJECTIVE

In patients with type 1 diabetes and end-stage renal disease, it is controversial whether a simultaneous pancreas-kidney (SPK) transplantation improves survival compared with kidney transplantation alone. We compared long-term survival in SPK and living- or deceased-donor kidney transplant recipients.

Mayer B. Davidson
Jul 1, 2015; 33:123-135
Feature Articles

Sara F. Morris
Dec 1, 2010; 28:12-18
Feature Articles

Andrew J.M. Boulton
Jan 1, 2005; 23:9-15
Feature Articles

Tina Vilsbøll
Jun 1, 2007; 30:1608-1610
BR Emerging Treatments and Technologies

Jing Hughes
Apr 1, 2015; 38:e55-e57
e-Letters: Observations

Denice S. Feig
Oct 1, 2011; 34:2329-2330
Editorial (See Rowan et al., p. 2279)

Vanita R. Aroda
Sep 1, 2019; 42:1724-1732
Emerging Therapies: Drugs and Regimens

Itamar Raz
Aug 1, 2013; 36:S139-S144
Diabetes Pathophysiology

Alison B. Evert
May 1, 2019; 42:731-754
Continuing Evolution of Nutritional Therapy for Diabetes

OBJECTIVE

The long-term influences of sex hormone administration on insulin sensitivity and incretin hormones are controversial. We investigated these effects in 35 transgender men (TM) and 55 transgender women (TW) from the European Network for the Investigation of Gender Incongruence (ENIGI) study.

OBJECTIVE

Topical oxygen has been used for the treatment of chronic wounds for more than 50 years. Its effectiveness remains disputed due to the limited number of robust high-quality investigations. The aim of this study was to assess the efficacy of multimodality cyclical pressure Topical Wound Oxygen (TWO2) home care therapy in healing refractory diabetic foot ulcers (DFUs) that had failed to heal with standard of care (SOC) alone.

OBJECTIVE

To examine the effect of combination therapy with canagliflozin plus liraglutide on HbA_1c, endogenous glucose production (EGP), and body weight versus each therapy alone.

OBJECTIVE

The vast number of antihyperglycemic medications and growing amount of evidence make clinical decision making difficult. The aim of this study was to investigate the safety of antihyperglycemic dual and triple therapies for type 2 diabetes management with respect to major adverse cardiovascular events, severe hypoglycemia, and all-cause mortality in a real-life clinical setting.

A 29 years old female presented to us in the metabolic clinic of the University of Port Harcourt Teaching Hospital (UPTH) on account of a week history of easy fatigability, weakness, and lower extremity muscle cramps associated with numbness and tingling sensation in the peri-oral area, fingers and toes. Two weeks prior to the onset of her presenting symptoms, she had visited a local pharmaceutical shop on account of a distressing epigastric discomfort and was subsequently placed on daily oral omeprazole 20mg daily for a month by a pharmacist. She had been on the omeprazole medication for two weeks before her present symptoms manifested. Her past medical history was not suggestive of hypoparathyroidism nor pancreatitis. She was married with three children and has an uneventful family, social and obstetric histories. On examination, she was a healthy well-oriented young female with positive Trousseau’s, Chvostek’s and epigastric tenderness signs. Further Laboratory evaluation revealed she had low plasma magnesium, low plasma albumin-corrected calcium, and low serum parathyroid hormone levels, while other laboratory parameters were essentially normal. A diagnosis of omeprazole-induced electrolyte disorders (hypomagnesaemia and hypocalcaemia) associated with hypoparathyroidism was made following the review of her clinical examination and laboratory findings. She was subsequently managed with oral magnesium supplements following the withdrawal of the omeprazole medication (replaced with oral ranitidine), monitored weekly, and full recovery was achieved after three weeks.

Cognitive-behavioral therapy improved both symptoms and markers of senescence in people with anxiety

-- Read more on ScientificAmerican.com

OBJECTIVE

To investigate the role of epigenetics in statins’ diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood.

Joseph A. Granata
Jan 1, 2015; 33:14-19
Feature Articles

Sara F. Morris
Dec 1, 2010; 28:12-18
Feature Articles

Stephen Brunton
Apr 1, 2019; 37:105-106
Editorials

Andrew J.M. Boulton
Jan 1, 2005; 23:9-15
Feature Articles

Jane K. Dickinson
Jan 1, 2017; 35:51-54
Commentary

John B. Buse
Jul 1, 2002; 20:
Feature Articles

Irl B. Hirsch
Apr 1, 2005; 23:78-86
Practical Pointers

The June 2020 issue of History of Psychiatry is now online. Full details follow below: “Wild melancholy. On the historical plausibility of a black bile theory of blood madness, or hæmatomania,” Jan Verplaetse. Abstract: Nineteenth-century art historian John Addington Symonds coined the term hæmatomania (blood madness) for the extremely bloodthirsty behaviour of a number of … Continue reading New History of Psychiatry: Melancholy, Madness, Chinese Psychiatry, Psychedelic Therapy, and More →

Two forthcoming pieces in History of the Human Sciences may be of interest to AHP readers. Full details below. “Cold War Pavlov: Homosexual aversion therapy in the 1960s,” by Kate Davison. Abstract: Homosexual aversion therapy enjoyed two brief but intense periods of clinical experimentation: between 1950 and 1962 in Czechoslovakia, and between 1962 and 1975 … Continue reading Forthcoming in HHS: Homosexual Aversion Therapy, Comte on Organism-Environment Relationships →

One of the primary reasons people seek therapy is to get help with mental health issues. Some of the more common mental disorders affecting individuals today include depression, anxiety, post traumatic stress (PTSD), phobias, addiction, and attention deficit hyperactivity (ADHD). Depending on the type and intensity of your issue, your therapist may adjust his treatment […]

The coronavirus pandemic is affecting billions of people around the world today. Coronavirus, now called covid 19, is a type of virus that is usually found in animals and is rarely transmitted to humans. According to reports from the World Health Organization, covid 19 likely originated from a seafood and meat market in Wuhan, China, […]

Telephone therapy has taken on greater significance in the mental health industry in wake of the covid-19 pandemic. While some individuals may have avoided telephone therapy in the past, the temporary closure of mental health offices and the necessity of social distancing have resulted in an increasing number of people asking for more information on […]

Although mental health is just as important as physical health in promoting overall well-being, many insurance companies in the past did not agree with that viewpoint. This is shown by the fact that, for many years,  a large percentage of insurers provided better insurance coverage for physical issues than mental health issues. However, in 2008, […]

Depression is one of the most common mental health issues in the United States. In fact, according to the National Institutes of Mental Health, 1 in 14 Americans experienced an episode of major depression in the last year alone. Given the circumstances surrounding the current COVID-19 coronavirus pandemic, many in the mental health community predict that the number will be even higher this year because these circumstances are creating a “perfect storm” of depression risks. The widespread prevalence of depression has a lot of implications for our lives, even if we don’t personally have depression ourselves. Many of us will have loved ones, such as a romantic partner, who develops depression at some point. In these situations, it’s common for people to wonder how they can help their partner most effectively. So what should they do?

As a practicing sex therapist, I often see two partners legitimately trying to bridge a satisfaction gap between each other, but they can’t seem to get the moves just right. If left unchecked, this can lead to resentment and conflict; however, couples who figure out how to speak to each other sexually (both verbally and nonverbally) have the highest success in terms of finding something that works for both of them. Making an environment conducive to this sort of positive growth requires a little bit of effort and the ability to listen. Drawing on my clinical experience, here are my top tips for increasing sexual satisfaction:

Paris : G. Steinheil, 1893.

Wien : M. Perles, 1878.

Wien : Urban & Schwarzenberg, 1893-1895.