Functional compensation between hematopoietic stem cell clones in vivo.

In most organ systems, regeneration is a coordinated effort that involves many stem cells, but little is known about whether and how individual stem cells compensate for the differentiation deficiencies of other stem cells. Functional compensation is critically important during disease progression and treatment. Here, we show how individual hematopoietic stem cell (HSC) clones heterogeneously compensate for the lymphopoietic deficiencies of other HSCs in a mouse. This compensation rescues the overall blood supply and influences blood cell types outside of the deficient lineages in distinct patterns. We find that highly differentiating HSC clones expand their cell numbers at specific differentiation stages to compensate for the deficiencies of other HSCs. Some of these clones continue to expand after transplantation into secondary recipients. In addition, lymphopoietic compensation involves gene expression changes in HSCs that are characterized by increased lymphoid priming, decreased myeloid priming, and HSC self-renewal. Our data illustrate how HSC clones coordinate to maintain the overall blood supply. Exploiting the innate compensation capacity of stem cell networks may improve the prognosis and treatment of many diseases.

Implementing a Chronic Wound Care Workshop for Internal Medicine Residents.

OBJECTIVE: To determine the feasibility of a piloted wound care curriculum within a busy internal medicine (IM) curriculum. METHODS: This prospective pilot study was conducted with 89 IM residents at an academic teaching hospital. The residents were provided a 90-minute workshop in chronic wound care. They anonymously completed a clinical vignette to target practice behavior prior to the workshop. The workshop was mixture of didactic and hands-on practice of sharp debridement and wound dressing selection. Three months later, the residents completed the same clinical vignette along with questions on changes and barriers to change in their practice. MAIN OUTCOME MEASURES: Change in behavior of chronic wound care management, measurements of barriers to change in participant continuity clinics. MAIN RESULTS: Of the participants, 57 residents (64%) and 25 residents (28%) completed a pre- and postvignette, respectively. Ten (40%) of the postvignette respondents stated that they had made changes in their care. Barriers to change included having a supervising attending physician who is not comfortable with wound care, a lack of wound care resources available in clinic, and a lack of confidence even after the session. CONCLUSIONS: It is feasible to insert a chronic wound care education into a busy IM curriculum. Future efforts will be aimed at assessing the wound care needs/resources of the IM outpatient clinics, addressing the comfort of the supervising attending physicians and residents with wound care, and focusing the curriculum on high-yield interventions.

Venous Leg Ulcers: The Need to Incorporate Age-Friendly 4M's in Management.

Venous leg ulcers develop due to a complex set of conditions routed in lower extremity edema and inflammation. Even though older adults are disproportionally affected by these wounds, the guidelines discuss best practices without keeping in mind the age-friendly 4M's-what Matters Most, Mobility, Medications, and Mentation/Mood. This article reviews the management and treatment of venous leg ulcers, but with a geriatric medicine focus. Compression therapy, mobility optimization, and social isolation reduction are highlighted for our older adult population.

The Challenge of Chronic Wounds in Older Adults.

Care for the older patient living with a chronic wound comes with challenges not seen in younger patients. The aging skin, impacted by the environment and intrinsic physiologic changes, makes it susceptible to injury and poor healing. Likewise, older adults' goals with regards to wound healing may vary depending on their functional abilities and quality of life. The clinician must pay attention to these nuances and collaborate with the older patient in developing a treatment plan. Careful systematic description, documentation, and communication with the patient/caregiver aids the clinician in tracking the treatment goals and potentially reducing medical liability risk.

Malunions following lower extremity fractures in veterans with a spinal cord injury/disorder.

BACKGROUND: Nearly 50% of all persons with a spinal cord injury/disorder (SCI/D) will sustain an osteoporotic fracture sometime in their life, with lower extremity fractures being the most common. There are a number of complications that can occur post fracture, including fracture malunion. To date, there have been no dedicated investigations of malunions among persons with SCI/D. OBJECTIVES: The primary objective of this study was to identify risk factors associated with fracture malunion among fracture-related (type of fracture, fracture location, initial fracture treatment) and SCI/D-related factors. Secondary objectives were to describe treatment of fracture malunions and complications following these malunions. METHODS: Veterans with SCI/D with an incident lower extremity fracture and subsequent malunion from Fiscal Year (FY) 2005-2015 were selected from the Veteran Health Administration (VHA) databases using International Classification of Diseases, 9th edition (ICD-9) codes for lower extremity fractures and malunion. These fracture malunion cases underwent electronic health record (EHR) review to abstract information on potential risk factors, treatments and complications for malunion. Twenty-nine cases were identified with a fracture malunion with 28 of them successfully matched with Veterans with a lower extremity fracture during FY2005-FY2014 without a malunion (matched 1:4) based on having an outpatient utilization date of care within 30 days of the fracture case. There was trend towards more nonsurgical treatment in the malunion group (n = 27, 96.43%) compared to the control group (n = 101, 90.18%) (P = 0.05), though fracture treatment proved not to be not associated with developing a malunion in univariate logistic regression analyses (OR = 0.30; 95% CI: 0.08-1.09). In multivariate analyses, Veterans with tetraplegia were significantly less likely (approximately 3-fold) to have a fracture malunion (OR = 0.38; 95% CI: 0.14-0.93) compared to those with paraplegia. Fracture malunion was significantly less likely to occur for fractures of the ankle (OR = 0.02; 95% CI: 0-0.13) or the hip (OR = 0.15; 95% CI: 0.03-0.56) compared to femur fractures. Fracture malunions were rarely treated. The most common complications following malunions were pressure injuries (56.3%) followed by osteomyelitis (25.0%). CONCLUSIONS: Persons with tetraplegia as well as fractures of the ankle and hip (compared to the femur) were less likely to develop a fracture malunion. Attention to prevention of avoidable pressure injuries following a fracture malunion is important.

Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.

Polyploidy road to therapy-induced cellular senescence and escape.

Therapy-induced cellular senescence (TCS), characterized by prolonged cell cycle arrest, is an in vivo response of human cancers to chemotherapy and radiation. Unfortunately, TCS is reversible for a subset of senescent cells, leading to cellular reproliferation and ultimately tumor progression. This invariable consequence of TCS recapitulates the clinical treatment experience of patients with advanced cancer. We report the findings of a clinicopathological study in patients with locally advanced non-small cell lung cancer demonstrating that marker of in vivo TCS following neoadjuvant therapy prognosticate adverse clinical outcome. In our efforts to elucidate key molecular pathways underlying TCS and cell cycle escape, we have previously shown that the deregulation of mitotic kinase Cdk1 and its downstream effectors are important mediators of survival and cell cycle reentry. We now report that aberrant expression of Cdk1 interferes with apoptosis and promotes the formation of polyploid senescent cells during TCS. These polyploid senescent cells represent important transition states through which escape preferentially occurs. The Cdk1 pathway is in part modulated differentially by p21 and p27 two members of the KIP cyclin-dependent kinase inhibitor family during TCS. Altogether, these studies underscore the importance of TCS in cancer therapeutics.

Bilateral Subluxation of Microspherophakic Lens in a Child with Cohen Syndrome.

Cohen Syndrome is a rare autosomal recessive condition characterized by facial abnormalities with or without microcephaly, non-progressive intellectual delay, hypotonia, ophthalmic abnormalities, and neutropenia. Due to its low incidence and variable presentation, much about the disorder, including ophthalmic manifestations, is not fully understood. Here, we present the first documented case of a 5-year-old Amish child with Cohen Syndrome who presented with bilateral subluxation of microspherophakic lenses - rare findings themselves, let alone coexisting in a patient with a rare genetic syndrome. The child underwent bilateral lensectomy and is being managed with aphakic spectacles.

Risk Factors and Consequences of Lower Extremity Fracture Nonunions in Veterans With Spinal Cord Injury.

We used Veterans Health Administration (VHA) national administrative data files to identify a cohort (fiscal years 2005-2014) of veterans with spinal cord injuries and disorders (SCID) to determine risk factors for and consequences of lower extremity fracture nonunions. Odds ratios (OR) for fracture nonunion were computed using multivariable-adjusted logistic regression models. We identified three risk factors for nonunion: (i) older age (OR = 2.29; 95% confidence interval [CI] 1.21-4.33), (ii) longer duration of SCID (OR = 1.02; 95% CI 1.00-1.04), and (iii) fracture site (distal femur), with OR (comparison distal femur) including distal tibia/fibula (OR = 0.14; 95% CI 0.09-0.24), proximal tibia/fibula (OR = 0.19; 95% CI 0.09-0.38), proximal femur (OR = 0.10; 95% CI 0.04-0.21), and hip (OR = 0.13; 95% CI 0.07-0.26). Nonunions resulted in multiple complications, with upwards of 1/3 developing a pressure injury, 13% osteomyelitis, and almost 25% requiring a subsequent amputation. Our data have identified a high-risk population for fracture nonunion of older veterans with a long duration of SCID who sustain a distal femur fracture. In view of the serious complications of these nonunions, targeted interventions in these high-risk individuals who have any signs of delayed union should be considered. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Survivin and escaping in therapy-induced cellular senescence.

Therapy-induced accelerated cellular senescence (ACS) is a reversible tumor response to chemotherapy that is likely detrimental to the overall therapeutic efficacy of cancer treatment. To further understand the mechanism by which cancer cells can escape the sustained cell cycle arrest in ACS, we established a tissue culture model, in which the p53-null NCI-H1299 cells can be induced into senescence by an abbreviated exposure to a chemotherapeutic agent. Previously, we have reported that senescent cells overexpress Cdc2/Cdk1 when they bypassed the prolonged arrest and their viability is dependent on Cdc2/Cdk1 kinase activity. In our study, we show that human survivin is the immediate downstream effector of the Cdc2/Cdk1 mediated survival signal. Survivin cooperates with Cdc2/Cdk1 to inhibit apoptosis following chemotherapy and promote senescence escape. Using HIV-1 TAT peptides to disrupt survivin phosphorylation by Cdc2/Cdk1, we also found that phosphorylated survivin is necessary both for the escape of senescent cells and for maintenance of subsequent viability after bypassing senescence. These results further propose survivin as an important determinant of senescence reversibility and as a putative molecular target to enforce cell death in ACS.

Nicotinamide-Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds.

Ponatinib is a multikinase inhibitor that is used to treat chronic myeloid leukemia patients harboring mutated ABL1(T315I) kinase. Due to the potent inhibition of FLT3, RET, and fibroblast growth factor receptors (FGFRs), it is also being evaluated against acute myeloid leukemia (AML), biliary, and lung cancers. The multikinase inhibition profile of ponatinib may also account for its toxicity, thus analogs with improved kinase selectivity or different kinase inhibition profiles could be better tolerated. The introduction of nitrogen into drug compounds can enhance efficacy and drug properties (a concept called "necessary nitrogen"). Here, we introduce additional nitrogen into the benzamide moiety of ponatinib to arrive at nicotinamide analogs. A nicotinamide analogue of ponatinib, HSN748, retains activity against FLT3, ABL1, RET, and PDGFRα/ß but loses activity against c-Src and P38α. MNK1 and 2 are key kinases that phosphorylate eIF4E to regulate the protein translation complex. MNK also modulates mTORC1 signaling and contributes to rapamycin resistance. Inhibitors of MNK1 and 2 are being evaluated for anticancer therapy. Ponatinib is not a potent inhibitor of MNK1 or 2, but the nicotinamide analogs are potent inhibitors of MNKs. This illustrates a powerful demonstration of the necessary nitrogen concept to alter both the potency and selectivity of drugs.

Potently inhibiting cancer cell migration with novel 3H-pyrazolo[4,3-f]quinoline boronic acid ROCK inhibitors.

Rho-associated protein kinases (ROCKs) are ubiquitously expressed in most adult tissues, and are involved in modulating the cytoskeleton, protein synthesis and degradation pathways, synaptic function, and autophagy to list a few. A few ROCK inhibitors, such as fasudil and netarsudil, are approved for clinical use. Here we present a new ROCK inhibitor, boronic acid containing HSD1590, which is more potent than netarsudil at binding to or inhibiting ROCK enzymatic activities. This compound exhibits single digit nanomolar binding to ROCK (Kds < 2 nM) and subnanomolar enzymatic inhibition profile (ROCK2 IC50 is 0.5 nM for HSD1590. Netarsudil, an FDA-approved drug, inhibited ROCK2 with IC50 = 11 nM under similar conditions). Whereas netarsudil was cytotoxic to breast cancer cell line, MDA-MB-231 (greater than 80% growth inhibition at concentrations greater than 5 µM), HSD1590 displayed low cytotoxicity to MDA-MB-231. Interestingly, at 1 µM HSD1590 inhibited the migration of MDA-MB-231 whereas netarsudil did not.

Putative association of the single nucleotide polymorphisms in RASSF1A promoter with Korean lung cancer.

SUMMARY: The RASSF1 gene, a putative tumor suppressor gene located on human chromosome 3p21, has attracted a great deal of attention because of frequent allelic loss and gene silencing via promoter hypermethylation in a variety of human malignancies. To evaluate the role of RASSF1A gene in lung cancer risk, genotypes of the RASSF1A promoter region (-710 C>T and -392T>C) were determined in 410 lung cancer patients and 410 normal subjects. Furthermore, to examine potential effects of the common haplotypes (C-C, T-T and C-T haplotypes) on RASSF1A transcription, luciferase reporter assays were performed in H2009 and H358 non-small cell lung cancer (NSCLC) cell lines. We found that ht2 C-T haplotype was associated with susceptibility to the risk of lung cancer in dominant (odds ratio (OR): 0.69; 95% CI: 0.46-0.99) model. In particular, we found that C-T haplotype showed a decreased risk of lung cancer in males (codominant OR: 0.59; 95% CI: 0.38-0.93 and dominant OR: 0.58; 95% CI: 0.35-0.96) and in smokers (codominant OR: 0.58; 95% CI: 0.36-0.93 and dominant OR: 0.56; 95% CI: 0.33-0.96). Interestingly, C-T haplotype induced transcriptional activity by 50-60% compared with other haplotypes in NSCLC cell lines. These results suggest that RASSF1A promoter polymorphisms affect RASSF1A expression, further contributing to the genetic susceptibility to lung cancer.

Epiploic appendagitis: A rare cause of acute abdomen.

Epiploic appendagitis is a rare cause of acute abdomen that often manifests with acute onset of pain in the left or right lower quadrant. Its symptoms can mimic and be mistaken for acute diverticulitis, appendicitis, or omental infarction. In this case report, we discuss a 65-year-old woman who presented with sharp right upper and lower quadrant abdominal pain, for which she had an emergent abdominal computed tomography (CT) scan. On CT images, epiploic appendagitis will appear as oval lesions with a central area of fat attenuation, accompanied by surrounding inflammation. Ultrasound and magnetic resonance imaging are more often used to evaluate acute abdominal pain in the pediatric and obstetric populations, so the respective findings of acute epiploic appendagitis must be recognized in those examinations as well. Despite the rarity of the condition and its common omission from differential diagnoses, the ability to recognize and diagnose epiploic appendagitis from its imaging is important for radiologists, especially considering its potential complications. If not diagnosed correctly, epiploic appendagitis can result in unnecessary hospital admission and patient workup, antibiotic use, dietary restrictions, and perhaps even unnecessary surgery. In this case, the diagnosis of epiploic appendagitis using CT allowed the patient to avoid surgery and other invasive treatment, and the patient was eventually discharged on conservative medical management.

Implementing a Chronic Wound Care Curriculum for Internal Medicine Residents.

OBJECTIVE: The objective of this study was to determine if participation in a practice-based learning session would change the residents' reported wound care practice. METHODS: A 90-minute didactic and skills workshop in chronic wound care was provided to 89 internal medicine (IM) residents divided into 4 groups, who were asked to complete an anonymous clinical vignette survey prior to the session and again 3 months after the practice-based learning session. RESULTS: Comparisons of the pretest and posttest scores (Mann-Whitney U Test) showed only ordering moisture-retentive dressing changed significantly. Residents reported likelihood of preventing/managing wounds in their future career on a 10-point Likert scale (mean 4.92). CONCLUSION: Future directions aimed at assessing the wound care needs/resources of the IM outpatient clinics, the comfort of the supervising clinicians and residents, and targeting the curriculum to those most likely to benefit should be addressed before further refining the curriculum.

Storytelling in person-centred care.

Storytelling is a powerful tool that can be used successfully to pass on knowledge, wisdom and expertise from educators to students. A story is more easily remembered and new concepts in nursing taught in story form are understood more readily. By the same token, the story of a resident's history allows caregivers to really understand who that person is and was, and in turn provide the care that will suit the unique needs of that resident. The person-centered care concept revolves around this uniqueness of person and the process of storytelling serves the understanding of the resident, the crafting of the care package itself, and communicating that knowledge to other caregivers.

Transplantation Dose Alters the Differentiation Program of Hematopoietic Stem Cells.

Hematopoietic stem cell (HSC) transplantation is the most prevalent stem cell therapy, but it remains a risky procedure. To improve this treatment, it is important to understand how transplanted stem cells rebuild the blood and immune systems and how this process is impacted by transplantation variables such as the HSC dose. Here, we find that, in the long term following transplantation, 70%-80% of donor-HSC-derived clones do not produce all measured blood cell types. High HSC doses lead to more clones that exhibit balanced lymphocyte production, whereas low doses produce more T-cell-specialized clones. High HSC doses also produce significantly higher proportions of early-differentiating clones compared to low doses. These complex differentiation behaviors uncover the clonal-level regeneration dynamics of hematopoietic regeneration and suggest that transplantation dose can be exploited to improve stem cell therapy.

Nonadherence to Antihypertensive Medication Among Hypertensive Adults in the United States─HealthStyles, 2010.

Nonadherence, or not taking medications as prescribed, to antihypertensive medications has been associated with uncontrolled hypertension. The authors analyzed data from HealthStyles 2010 to assess medication nonadherence among adults with hypertension. The overall prevalence of hypertension was 27.4% and the prevalence of nonadherence was 30.5% among hypertensive adult respondents. Nonadherence rates were highest among younger adults (aged 18-44 years), Hispanics, those who reported lowest annual income (<$25,000), and those who reported depression. The most common reason stated for nonadherence was "I cannot afford the medication" (35.1%). A multivariate logistic regression model showed age, race, and household income to be associated with nonadherence. These findings suggest that certain subgroups are more likely to report barriers to adherence. Interventions to support the management of hypertension should consider the identification of certain at-risk subgroups and utilize community and clinical evidenced-based resources to improve long-term control.