Lysyl oxidase like‐2 (LOXL2) plays a central role in fibrogenesis and is elevated in the serum and liver of patients with primary sclerosing cholangitis (PSC). We evaluated the safety and efficacy of ...simtuzumab, a monoclonal antibody directed against LOXL2, in patients with PSC. Patients with compensated liver disease caused by PSC were randomized 1:1:1 to receive weekly subcutaneous injections of simtuzumab 75 mg, simtuzumab 125 mg, or placebo for 96 weeks. The primary efficacy endpoint was mean change in hepatic collagen content assessed by morphometry between baseline and week 96. Additional endpoints included change in Ishak fibrosis stage and the frequency of PSC‐related clinical events. Overall, 234 patients were randomized and started treatment. At week 96, the mean change from baseline in hepatic collagen content was –0.5% for patients receiving simtuzumab 75 mg (P = 0.73 versus placebo), +0.5% for patients receiving simtuzumab 125 mg (P = 0.33 versus placebo), and 0.0 for patients receiving placebo. Compared with placebo, neither dose of simtuzumab led to significant reductions in Ishak fibrosis stage, progression to cirrhosis, or frequency of clinical events. Overall, 80 (34%) patients had fibrosis progression and 47 (20%) experienced PSC‐related clinical events. In a multivariate model of baseline factors, PSC‐related clinical events were more frequent in patients with advanced fibrosis (hazard ratio HR, 2.03; 95% confidence interval CI, 1.02‐4.06; P = 0.045), higher alkaline phosphatase (HR per 10 U/L, 1.01; 95% CI, 1.00‐1.02; P = 0.015), and higher enhanced liver fibrosis score (HR per unit, 1.26; 95% CI, 0.98‐1.61; P = 0.073). Overall, rates of adverse events and laboratory abnormalities were similar between groups. Conclusion: Treatment with the LOXL2 inhibitor simtuzumab for 96 weeks did not provide clinical benefit in patients with PSC.
Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells ...influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system.
The correlation between hyperamylasemia and acute pancreatitis was discovered in 1929, yet another test, lipase, was shown to provide better diagnostic performance in the late 1980s and early 1990s. ...Subsequent studies demonstrated co-ordering amylase with lipase did not provide additional benefit, only added cost. We sought to investigate the impact of studies advocating for the obsolescence of amylase on its clinical demand. We reviewed 1.3 million reportable results for amylase over 14 years (2009-2022). The trend in utilization of amylase over this period declined by 66% along a linear trajectory (R2 = 0.97). Despite demand for amylase decreasing by an average of 17,003 tests per year, the last year of the study (2022) recorded over 100,000 results for amylase. By interpolating the decline of amylase until the utilization reached zero, we calculated amylase orders will continue for 6 more years until 2028. Tests for creatinine and lipase changed <3% over the same period. Despite a multitude of studies advocating for the obsolescence of amylase, robust demand continues. Many important clinical guidelines, a source many practicing physicians rely on, have yet to acknowledge the preference for lipase over amylase. They frequently treat the two tests as equivalent, neglecting their head-to-head comparison studies and subsequent studies advocating against co-ordering both tests simultaneously. To expedite the obsolescence of amylase, which we anticipate lasting 46 years in our case study from its initial call for obsolescence to the last orders placed, metrics created specifically to monitor the utilization of unnecessary tests are also needed.
Physician turnover places a heavy burden on the healthcare industry, patients, physicians, and their families. Having a mechanism in place to identify physicians at risk for departure could help ...target appropriate interventions that prevent departure. We have collected physician characteristics, electronic health record (EHR) use patterns, and clinical productivity data from a large ambulatory based practice of non-teaching physicians to build a predictive model. We use several techniques to identify possible intervenable variables. Specifically, we used gradient boosted trees to predict the probability of a physician departing within an interval of 6 months. Several variables significantly contributed to predicting physician departure including tenure (time since hiring date), panel complexity, physician demand, physician age, inbox, and documentation time. These variables were identified by training, validating, and testing the model followed by computing SHAP (SHapley Additive exPlanation) values to investigate which variables influence the model's prediction the most. We found these top variables to have large interactions with other variables indicating their importance. Since these variables may be predictive of physician departure, they could prove useful to identify at risk physicians such who would benefit from targeted interventions.
More than 85% of advanced breast cancer patients suffer from metastatic bone lesions, yet the mechanisms that facilitate these metastases remain poorly understood. Recent studies suggest that ...tumor-derived factors initiate changes within the tumor microenvironment to facilitate metastasis. However, whether stromal-initiated changes are sufficient to drive increased metastasis in the bone remains an open question. Thus, we developed a model to induce reactive senescent osteoblasts and found that they increased breast cancer colonization of the bone. Analysis of senescent osteoblasts revealed that they failed to mineralize bone matrix and increased local osteoclastogenesis, the latter process being driven by the senescence-associated secretory phenotype factor, IL-6. Neutralization of IL-6 was sufficient to limit senescence-induced osteoclastogenesis and tumor cell localization to bone, thereby reducing tumor burden. Together, these data suggest that a reactive stromal compartment can condition the niche, in the absence of tumor-derived signals, to facilitate metastatic tumor growth in the bone.
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•Stromal changes in the bone drive tumor cell seeding and growth•IL-6-expressing stromal cells are present in human bone•Senescent osteoblasts drive increased osteoclastogenesis and tumor cell seeding•Senescent-derived IL-6 drives localized osteoclastogenesis and tumor cell growth
Luo et al. show that stromal-derived changes are sufficient to increase tumor cell colonization and metastatic growth in the bone. They report that senescent osteoblasts, and, in particular, the senescence-associated secretory phenotype factor IL-6 drives localized osteoclastogenesis and tumor cell growth.
High levels of collagen deposition in human and mouse breast tumors are associated with poor outcome due to increased local invasion and distant metastases. Using a genetic approach, we show that, in ...mice, the action of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2) in both tumor and tumor-stromal cells is critical for breast cancer metastasis yet does not affect primary tumor growth. In tumor cells, DDR2 in basal epithelial cells regulates the collective invasion of tumor organoids. In stromal cancer-associated fibroblasts (CAFs), DDR2 is critical for extracellular matrix production and the organization of collagen fibers. The action of DDR2 in CAFs also enhances tumor cell collective invasion through a pathway distinct from the tumor-cell-intrinsic function of DDR2. This work identifies DDR2 as a potential therapeutic target that controls breast cancer metastases through its action in both tumor cells and tumor-stromal cells at the primary tumor site.
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•DDR2 activity in both tumor and stromal cells is critical for breast cancer metastasis•DDR2 regulates collective invasion/migration of basal K14+ breast tumor cells•In CAFs, DDR2 regulates tumor ECM production and collagen fiber remodeling•In CAFs, DDR2 enhances tumor collective invasion/migration
Using an in vivo genetic approach, Corsa et al. identify the actions of DDR2, a distinctive receptor tyrosine kinase activated by fibrillar collagens, in breast cancer metastasis. DDR2 functions in both tumor and stromal cells of primary tumors, affecting metastasis but not tumor growth.
Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI ...stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stemcells were lost in fedmice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked byLgr5, Bmi1,orHopXexpression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.
The Hippo pathway controls organ growth and is implicated in cancer development. Whether and how Hippo pathway activity is limited to sustain or initiate cell growth when needed is not understood. ...The members of the AJUBA family of LIM proteins are negative regulators of the Hippo pathway. In mammalian epithelial cells, we found that AJUBA LIM proteins limit Hippo regulation of YAP, in proliferating cells only, by sequestering a cytosolic Hippo kinase complex in which LATS kinase is inhibited. At the plasma membranes of growth-arrested cells, AJUBA LIM proteins do not inhibit or associate with the Hippo kinase complex. The ability of AJUBA LIM proteins to inhibit YAP regulation by Hippo and to associate with the kinase complex directly correlate with their capacity to limit Hippo signaling during
Drosophila
wing development. AJUBA LIM proteins did not influence YAP activity in response to cell-extrinsic or cell-intrinsic mechanical signals. Thus, AJUBA LIM proteins limit Hippo pathway activity in contexts where cell proliferation is needed.
Coronavirus disease 2019 (COVID-19) has disrupted outpatient pediatrics, postponing well-child care to address immediate patient safety concerns. Screening for lead toxicity is a critical component ...of this care. Children may be at increased risk for lead exposure at home because of social restrictions. We present data on how COVID-19 restrictions have impacted lead screening in a primary care practice.
Lead testing data on 658 children in a primary care practice were analyzed to determine the effect of COVID-19 restrictions on lead screening rates, levels, and deficiencies.
Lead screening significantly decreased during peak restrictions, leading to increased screening deficiencies. Despite this decrease, screening lead levels increased during peak restrictions.
These data show how COVID-19 restrictions have disrupted routine care and highlight the importance of continued lead screening in at-risk populations. The electronic medical record can be leveraged to identify deficiencies to be targeted by quality improvement initiatives.
Collective motions of groups of cells are observed in many biological settings such as embryo development, tissue formation, and cancer metastasis. To effectively model collective cell movement, it ...is important to incorporate cell specific features such as cell size, cell shape, and cell mechanics, as well as active behavior of cells such as protrusion and force generation, contractile forces, and active biochemical signaling mechanisms that regulate cell behavior. In this paper, we develop a comprehensive model of collective cell migration in confluent epithelia based on the vertex modeling approach. We develop a method to compute cell-cell viscous friction based on the vertex model and incorporate RhoGTPase regulation of cortical myosin contraction. Global features of collective cell migration are examined by computing the spatial velocity correlation function. As active cell force parameters are varied, we found rich dynamical behavior. Furthermore, we find that cells exhibit nonlinear phenomena such as contractile waves and vortex formation. Together our work highlights the importance of active behavior of cells in generating collective cell movement. The vertex modeling approach is an efficient and versatile approach to rigorously examine cell motion in the epithelium.
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