c-Src-induced vascular malformations require localised matrix degradation at focal adhesions.

Endothelial cells lining the blood vessel wall communicate intricately with the surrounding extracellular matrix, translating mechanical cues into biochemical signals. Moreover, vessels require the capability to enzymatically degrade the matrix surrounding them, to facilitate vascular expansion. c-Src plays a key role in blood vessel growth, with its loss in the endothelium reducing vessel sprouting and focal adhesion signalling. Here, we show that constitutive activation of c-Src in endothelial cells results in rapid vascular expansion, operating independently of growth factor stimulation or fluid shear stress forces. This is driven by an increase in focal adhesion signalling and size, with enhancement of localised secretion of matrix metalloproteinases responsible for extracellular matrix remodelling. Inhibition of matrix metalloproteinase activity results in a robust rescue of the vascular expansion elicited by heightened c-Src activity. This supports the premise that moderating focal adhesion-related events and matrix degradation can counteract abnormal vascular expansion, with implications for pathologies driven by unusual vascular morphologies.

Endothelial c-Src Mediates Neovascular Tuft Formation in Oxygen-Induced Retinopathy.

Vascular retinopathy, characterized by abnormal blood vessel growth in the retina, frequently results in vision impairment or loss. Neovascular tufts, a distinctive pathologic feature of this condition, are highly leaky blood vessel structures, exacerbating secondary complications. Despite their clinical significance, the mechanisms underlying tuft development are not fully elucidated, posing challenges for effective management and treatment of vascular retinopathy. This study investigates the role of c-Src in neovascular tuft formation. Although c-Src has been acknowledged as a pivotal regulator in developmental angiogenesis within the retinal vasculature, its specific role in governing pathologic retinal angiogenesis remains to be fully understood. The oxygen-induced retinopathy model was used for neovascular tuft formation in both Cre-mediated vascular-specific c-Src knockout mice and wild-type littermates. High-resolution imaging and analysis of isolated retinas were conducted. c-Src depletion demonstrated a significant reduction in neovascular tufts within the oxygen-induced retinopathy model. This decrease in tuft formation was observed independently of any alterations in cell death, cell proliferation, or cell adhesion, and the absence of c-Src did not impact tuft pericyte coverage and junctional morphology. These findings underline the critical role of c-Src in the pathogenesis of neovascular tufts in vascular retinopathy. Understanding the molecular mechanisms involving c-Src may offer valuable insights for the development of targeted therapies aimed at mitigating vision-threatening complications associated with retinopathy.

Lupus nephritis in a transgender woman on cross-sex hormone therapy: a case for the role of oestrogen in systemic lupus erythematosus.

We present the case of a 22-year-old African American transgender women (male to female), who was admitted for fatigue, abdominal pain and lower extremity edema and was diagnosed with systemic lupus erythematosus (SLE) and lupus nephritis. Treatment with high-dose steroids and mycophenolate mofetil helped resolve her symptoms. She has remained off oestrogen therapy since admission and has not experienced any major complications. It is important to consider therapy outcomes in this specific patient population. A review of four other cases of transgender women on cross-sex hormone therapy who were diagnosed with lupus is also presented.

Does the frequency of molecular monitoring after tyrosine kinase inhibitor discontinuation affect outcomes of patients with chronic myeloid leukemia?

BACKGROUND: To the authors' knowledge, the optimal frequency of monitoring after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) has not been established. Data regarding the discontinuation of second-generation TKIs used in first-line treatment or after the failure of first-line treatment with TKIs are limited. Herein, the authors report real-world experience with "reduced frequency" molecular monitoring in patients with CML in all phases who discontinued treatment with imatinib, dasatinib, or bosutinib. METHODS: The records of patients who discontinued TKIs were reviewed. Patients who discontinued TKIs were monitored prospectively on an intended schedule of monthly blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 for 3 months, quarterly for 12 months, and every 6 months thereafter until loss of major molecular response (MMR). After loss of MMR, the TKI that previously was discontinued was reinitiated. RESULTS: Between January 2010 and September 2015, a total of 24 patients in chronic (21 patients), accelerated (2 patients), and lymphoid blast (1 patient) phase discontinued imatinib (16 patients), dasatinib (5 patients), or bosutinib (3 patients) used in the front-line treatment or beyond. Blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 was performed 1.3 ± 0.7 times within the first 3 months (24 patients) and 2.7 ± 1.4 times in the following 12 months (18 patients). With a median follow-up of 36.5 months (range, 3.2-67.4 months), the probabilities of treatment-free remission at 1 year and 2 years were 65.7% (95% confidence interval, 55.8%-75.6%) and 59.7% (95% confidence interval, 49.1%-70.3%), respectively. Loss of MMR was observed in 9 patients at a median of 2.8 months (range, 1.8-14.2 months) after discontinuation of TKIs. CONCLUSIONS: With the limitations of a small sample size, the results of the current study demonstrate that less frequent monitoring of BCR-ABL1 does not appear to affect outcomes, and that discontinuation of TKIs used as first-line treatment or beyond after resistance or intolerance to first-line treatment appears feasible. Cancer 2017;123:2482-88. © 2017 American Cancer Society.

Incidence and geographic distribution of adult acute leukemia in the state of Georgia.

OBJECTIVE: We investigated an apparent increase in acute lymphoblastic leukemia (ALL) referrals from northern Georgia to a tertiary care center located in Atlanta. METHODS: Cases reported to the Georgia Comprehensive Cancer Registry and the national Surveillance Epidemiology and End Results cancer registry between 1999 and 2008 were analyzed. Age-adjusted incidence rates were calculated for all of the counties and public health regions and were compared with national rates calculated using Surveillance Epidemiology and End Results 17 data. Cases of adult acute myeloid leukemia served as controls. RESULTS: Age-adjusted incidence rates of adult ALL (0.8/100,000) and acute myeloid leukemia (4.6/100,000) were comparable to the national rates (0.9 and 5.2, respectively). The age-adjusted incidence rate of ALL in northern Georgia was 1.1 (95% confidence interval 0.8-1.5) and was not affected by race. CONCLUSIONS: The observed increase in cases of ALL at our tertiary center results from a referral pattern rather than heterogeneous distribution of adult ALL across Georgia.

Macrophage ACE2 is necessary for SARS-CoV-2 replication and subsequent cytokine responses that restrict continued virion release.

Macrophages are key cellular contributors to the pathogenesis of COVID-19, the disease caused by the virus SARS-CoV-2. The SARS-CoV-2 entry receptor ACE2 is present only on a subset of macrophages at sites of SARS-CoV-2 infection in humans. Here, we investigated whether SARS-CoV-2 can enter macrophages, replicate, and release new viral progeny; whether macrophages need to sense a replicating virus to drive cytokine release; and, if so, whether ACE2 is involved in these mechanisms. We found that SARS-CoV-2 could enter, but did not replicate within, ACE2-deficient human primary macrophages and did not induce proinflammatory cytokine expression. By contrast, ACE2 overexpression in human THP-1-derived macrophages permitted SARS-CoV-2 entry, processing and replication, and virion release. ACE2-overexpressing THP-1 macrophages sensed active viral replication and triggered proinflammatory, antiviral programs mediated by the kinase TBK-1 that limited prolonged viral replication and release. These findings help elucidate the role of ACE2 and its absence in macrophage responses to SARS-CoV-2 infection.

Healing journeys: experiences of young Aboriginal people in an urban Australian therapeutic community drug and alcohol program.

Disproportionately high numbers of Aboriginal young people access residential alcohol and other drug programs in Australia. While demand is high, these programs often have low numbers of Aboriginal staff. Residential programs, however, generally offer supports that reflect features of Aboriginal health care - holistic, group-based, connected to local communities, and addressing determinants of health. The qualitative research outlined in this paper was a collaboration between a mainstream residential therapeutic community program and two Aboriginal community-controlled organisations, and Aboriginal young people and researchers, with Aboriginal research leadership. It used an Aboriginal healing framework to understand the experiences of 12 young Aboriginal people in the program, triangulated with 19 key informant interviews. This provided an opportunity to understand how Indigenous knowledge about healing related to mainstream programs and the experiences of Aboriginal young people. This moves beyond individualist and deficit-focused conceptions of youth alcohol and drug use and centres Aboriginal cultures as healing. Findings point to the need for critically self-reflective mainstream organisations, a larger Aboriginal workforce with leadership roles, partnerships with Aboriginal Elders and organisations, and an investment in Aboriginal community-controlled alcohol and other drug services.

Telemedicine in rheumatology care: A systematic review.

OBJECTIVE: The COVID-19 pandemic led to a sudden uptake of telemedicine in rheumatology. We analyzed the recent published literature on telemedicine for the diagnosis and management of inflammatory, non-inflammatory and/or autoimmune rheumatic diseases. METHODS: We performed a registered systematic search (CRD42020202063) for interventional or observational studies published between August 2015 and January 2022. We included studies of telemedicine that reported outcomes (e.g., satisfaction, disease activity, quality of life) in ten or more people with rheumatic disease. Reviewers screened manuscripts, extracted data, and assessed bias. RESULTS: Of the 2,988 potentially eligible studies, 36 reports were included: 27 observational studies, 7 randomized clinical trials, and 2 controlled clinical trials. Studies focused on general rheumatology (n = 18), rheumatoid arthritis (n = 9), gout (n = 3), osteoarthritis (n = 2), unspecified inflammatory arthritis (n = 1), osteoporosis (n = 2), and systemic lupus erythematosus (n = 1). Patient satisfaction with telemedicine was the most common reported outcome (n = 23) with majority of studies demonstrating high levels of satisfaction. Among interventional studies, the effect of telemedicine on the primary outcomes varied, with most finding that telemedicine was as good as usual / in-person care for disease activity control, patient satisfaction, total societal costs, and other patient reported outcomes. Effectiveness and feasibility were high across studies, though most demonstrated a high risk of bias. Meta-analysis was not feasible given the heterogeneity of interventions and outcome instruments utilized. CONCLUSION: Although the number of studies to date is low, telemedicine may be an effective mode to deliver care for people with rheumatic diseases. Most studies demonstrated limitations due to study design and risk of bias. Randomized clinical studies are needed to determine best uses of telemedicine for the diagnosis and management of rheumatic conditions.

Prevalence and predictors of food insecurity in migrant farmworkers in Georgia.

We examined the prevalence of food insecurity in migrant farmworkers in Georgia. Of these workers 62.83% did not have enough food, and non-H-2A workers had an adjusted risk of food insecurity almost 3 times higher than did H-2A workers. Lack of access to cooking facilities, transportation problems, and having children were additional risk factors. Migrant farmworkers are at extreme risk for food insecurity, although being an H-2A guestworker was protective within this population. Policy interventions are needed to protect these vulnerable farmworkers.

Cerebral Toxoplasmosis in a Rheumatoid Arthritis Patient on Immunosuppressive Therapy.

Cerebral toxoplasmosis is a life-threatening infection most commonly found in immunocompromised hosts such as acquired immunodeficiency syndrome (AIDS) or transplant patients. However, it is not known to affect patients with chronic inflammatory disorders on immunosuppressive therapy. We describe the case of a 70-year-old female with rheumatoid arthritis (RA) on chronic therapy with methotrexate and infliximab, who presented to the hospital after two weeks of right-sided weakness. Imaging revealed bilateral ring-enhancing lesions in the basal ganglia (left greater than right). A diagnosis of cerebral toxoplasmosis was made on brain biopsy. Apart from the immunosuppressive therapy and owning a cat, she had no other risk factors for developing the infection. The patient's immunosuppressive medications were discontinued, and she was started on high-dose trimethoprim-sulfamethoxazole (TMP-SMX). Upon literature review using PubMed, we found seven other published reports on similar cases of toxoplasmosis in RA patients on immunosuppressive therapy; however, there was a lack of recommendations for diagnosis, treatment, and prophylaxis in this patient population. With the growing use of immunosuppressive therapies in chronic inflammatory disorders, further data is needed regarding the management of toxoplasmosis in these patients. This case report is an investigation of the relationship between immunosuppressive medications in RA patients and cerebral toxoplasmosis and an exploration of the available recommendations for its management.

Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors.

We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4-190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1-53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.

The safety of Bosutinib for the treatment of chronic myeloid leukemia.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) are a potentially lifelong treatment for patients with chronic myeloid leukemia (CML). Adverse events (AEs) associated with TKIs are significant impediments in the daily life of patients that can impact compliance, and efficacy. Areas covered: This is a review on safety of bosutinib in the treatment of chronic phase CML. Data is extracted from the latest updates of bosutinib phase I/II and III trials. Expert opinion: Bosutinib is an effective agent against all phases of CML presently approved for the treatment in patients with resistance or intolerance to prior TKI therapy. Bosutinib has a unique toxicity profile characterized by early and transient diarrhea. Otherwise, the AE profile of bosutinib is comparable to other TKIs, with the exception of cardiovascular AEs that are infrequent in bosutinib-treated patients. Similar to other TKIs, the minimum effective dose of bosutinib remains unknown. Better definition of the optimal effective dose may spare, for those patients otherwise benefitting from treatment, unnecessary AEs.

Risk factors for vitamin D deficiency among veterans with and without HIV infection.

OBJECTIVES: We aimed to describe and compare the prevalence of vitamin D deficiency between HIV-negative and HIV-infected veterans in the southern United States, and to determine risk factors for vitamin D deficiency for HIV infected patients. METHODS: Cross-sectional, retrospective study including all patients followed at the Atlanta VA Medical Center with the first 25-hydroxyvitamin D [25(OH)D] level determined between January 2007 and August 2010. Multivariate logistic regression analysis was used to determine risk factors associated with vitamin D deficiency (< 20 ng/ml). RESULTS: There was higher prevalence of 25(OH)D deficiency among HIV-positive compared to HIV-negative patients (53.2 vs. 38.5%, p <0.001). Independent risk factors for vitamin D deficiency in HIV + patients included black race (OR 3.24, 95% CI 2.28-4.60), winter season (OR 1.39, 95% CI 1.05-1.84) and higher GFR (OR 1.01, CI 1.00-1.01); increasing age (OR 0.98, 95% CI 0.95-0.98), and tenofovir use (OR 0.72, 95% CI 0.54-0.96) were associated with less vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency is a prevalent problem that varies inversely with age and affects HIV-infected patients more than other veterans in care. In addition to age, tenofovir and kidney disease seem to confer a protective effect from vitamin D deficiency in HIV-positive patients.

Bosutinib: a third generation tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia.

Bosutinib is an oral tyrosine kinase inhibitor (TKI) with very potent dual inhibitory activity against SRC and abelson gene. Bosutinib was approved in 2012 for the treatment of resistant Philadelphia chromosome positive chronic myeloid leukemia (CML). Bosutinib is a very effective TKI against all phases of intolerant or resistant CML regardless of the presence or absence of an abelson gene domain mutation, except for cases with detectable T315I or V299L. Bosutinib is overall well tolerated and associated with a unique, but manageable toxicity profile. Factors that influence the prescribing pattern of this drug are complex and include physicians', and increasingly patients and families' preference, patients' comorbid conditions, schedule of administration, as well as financial factors. This paper provides an overview of CML, the TKI market, pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of bosutinib.