Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly ...contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration.
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•Solid oxo-Re and oxo-Mo catalysts were evaluated for the deoxydehydration of 1,2-diols to olefins.•A silica-tethered catecholato oxo-rhenium catalyst had DODH activity comparable to ...its soluble analog.•Alkene yields with ReOx-SiO2, −Fe2O3, −Al2O3 were highest with PPh3, but H2 or CO were also effective.•Solid oxo-molybdenum catalysts had DODH activity with best selectivity for olefins with MoOx/Fe2O3.•Some reversible catalyst leaching occurred with Re-catecholate and MoOx-oxide catalysts.
Several new solid oxo-rhenium and oxo-molybdenum catalysts were tested for the deoxydehydration (DODH) of 1,2-diols to terminal olefins employing aromatic solvents and reaction temperatures of 150–200°C. A catecholato oxo-rhenium catalyst tethered to silica was prepared and found to have comparably high DODH activity to its soluble analog with triphenylphosphine as the reductant. Catalyst re-use and leach-test experiments show significant leaching into the liquid phase. Silica, ceria and, for the first time, alumina and iron oxide were tested as supports for perrhenate, with ceria producing the least active material in 1,2-decane diol DODH. Decene yields obtained with ReOx/SiO2, ReOx/Fe2O3, ReOx/Al2O3 were highest when triphenylphosphine was the reductant and reached 70−78% (at 90–100% conversion) at 150°C. These three catalysts were also effective with gaseous reductants H2 or CO. Leaching of rhenium species occurred for all supports and was most pronounced for SiO2. New solid oxo-molybdenum catalysts were synthesized. At 200°C, decene yields observed using MoOx/Fe2O3, MoOx/SiO2, MoOx/Al2O3, MoOx/TiO2 and MoOx/ZrO2 were comparable and did not exceed 20%. There were homogeneous contributions through leached molybdenum species.
Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells ...remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the four most common driver mutations of this disease. Similarly, sorted ductal cells carrying these genetic mutations can also form PDAC, thus experimentally proving that PDACs can originate from both human acinar and ductal cells. RNA-seq analysis reveal the transcriptional shift from normal acinar cells towards PDACs with enhanced proliferation, metabolic rewiring, down-regulation of MHC molecules, and alterations in the coagulation and complement cascade. By comparing PDAC-like cells with normal pancreas and PDAC samples, we identify a group of genes with elevated expression during early transformation which represent potential early diagnostic biomarkers.
Summary
There is an urgent need to improve access to safe surgical and anaesthetic care for children living in many low‐ and middle‐income countries. Providing quality training for healthcare workers ...is a key component of achieving this. The 3‐day Safer Anaesthesia from Education (SAFE)® paediatric anaesthesia course was developed to address the specific skills and knowledge required in this field. We undertook a project to expand this course across five East and Central African countries (Ethiopia, Kenya, Malawi, Uganda and Zambia) and train local faculty. This study reports the outcomes from course evaluation data, exploring the impact on knowledge, skills and behaviour change in participants. Eleven courses were conducted in a 15‐month period, with 381 participants attending. Fifty‐nine new faculty members were trained. Knowledge scores (0–50 scale) increased significantly from mean (SD) 37.5 (4.7) pre‐course to 43.2 (3.5) post‐course (p < 0.0001). Skills scores (0–10 scale) increased significantly from 5.7 (2.0) pre‐course to 8.0 (1.5) post‐course (p < 0.0001). One hundred and twenty‐six participants in Malawi, Uganda and Zambia were visited in their workplace 3–6 months later. Knowledge and skills were maintained at follow‐up, with scores of 41.5 (5.0) and 8.3 (1.4), respectively (p < 0.0001 compared with pre‐course scores). Content analysis from interviews with these participants highlighted positive behaviour changes in the areas of preparation, peri‐operative care, resuscitation, management of the sick child, communication and teaching. This study indicates that the SAFE paediatric anaesthesia course is an effective way to deliver training, and could be used to help strengthen emergency and essential surgical care for children as a component of universal health coverage.
Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels ...below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of 'covert' virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.
Central nervous system (CNS) relapse of acute lymphoblastic leukemia (ALL) is associated with a poor prognosis. However, prophylactic measures, including intrathecal (IT) methotrexate, reduce the ...incidence of CNS relapse in these patients considerably. Unfortunately, IT methotrexate can cause several neurologic complications, including transverse myelopathy; ie, the development of isolated spinal cord dysfunction over hours or days following the IT infusion of methotrexate, but in the absence of a compressive lesion. Transverse myelopathy following IT methotrexate is a well-established clinical phenomenon, but the histologic features have been described only very rarely. We report the autopsy findings from a 31-year-old man with a history of T-cell ALL who received prophylactic IT methotrexate in anticipation of a bone marrow transplant. Microscopic examination showed transverse necrosis of the thoracic cord, with massive infiltration by macrophages and lymphocytes, and perivascular lymphocytic infiltrates. There was cavitary necrosis of cervical and lumbar spinal cord involving the entire gray matter and focal white matter, as well as extensive subpial vacuolar degeneration of the dorsal and lateral columns.
Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes ...of UK patients treated with fulvestrant monotherapy at nine representative centres.
Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored.
Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21–95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0–1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0–5) prior lines of endocrine therapy and median 0 (range 0–6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1–88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0–88).
This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.
•Fulvestrant is licensed for the treatment of hormone receptor-positive advanced breast cancer in postmenopausal women.•One of the largest studied patient cohorts treated with fulvestrant, with data collection from nine UK centres.•Results confirm a modest radiological response rate even in a predominantly pretreated cohort.•Fair access to fulvestrant monotherapy in England should be standard to enable its use in patients most likely to benefit.
Plasma VLDL and LDL cholesterol were markedly elevated (>40-fold) in high-responding opossums, but moderately elevated (6-fold) in low-responding opossums after they had consumed a high-cholesterol ...and high-fat diet for 24 wk. In both high- and low-responding opossums, plasma triglycerides were slightly elevated, threefold and twofold, respectively. Dietary challenge also induced fatty livers in high responders, but not in low responders. We studied the lipid composition, histopathological features, and gene expression patterns of the fatty livers. Free cholesterol (2-fold), esterified cholesterol (11-fold), and triglycerides (2-fold) were higher in the livers of high responders than those in low responders, whereas free fatty acid levels were similar. The fatty livers of high responders showed extensive lobular disarray by histology. Inflammatory cells and ballooned hepatocytes were also present, as were perisinusoidal fibrosis and ductular proliferation. In contrast, liver histology was normal in low responders. Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders. The accumulation of hepatic cholesterol was concomitant with upregulation of the HMGCR gene and downregulation of the CYP27A1, ABCG8, and ABCB4 genes. Genes involved in inflammation (TNF, NFKB1, and COX2) and in oxidative stress (CYBA and NCF1) were upregulated. Upregulation of the growth factor genes (PDGF and TGFB1) and collagen genes (Col1A1, Col3A1, and Col4A1) was consistent with fibrosis. Some of the histological characteristics of the fatty livers of high-responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis.
The concentration and duration of antibodies (Ab) to SARS-CoV-2 infection predicts the severity of the disease and the clinical outcomes. Older people and those with HIV have impaired immune ...responses, worse outcomes after SARS-CoV-2 infection, and lower antibody responses after viral infection and vaccination. This study evaluated an Ab response to SARS-CoV-2 in people with HIV (PWH) and without HIV (HIV-) and its association with age.
A total of 23 COVID+PWH and 21 COVID+HIV- participants were followed longitudinally for 6 months post-mild COVID-19. Immunoglobin G (IgG) and immunoglobin M (IgM) Ab responses were measured by an in-house developed ELISA. Time points and HIV status interaction were analyzed using Poisson generalized estimating equations, and correlations were analyzed using non-parametric tests.
Median age in PWH was 55 years with 28.6% women, while in the HIV- group was 36 years with 60.9% women. The mean time from COVID-19 diagnosis to study enrollment was 16 days for PWH and 11 days for HIV-. The mean CD4+ T-cell count/μl for PWH was 772.10 (±365.21). SARS-CoV-2 IgM and IgG were detected at all time points and Ab response levels did not differ by HIV status (
> 0.05). At entry, age showed a weak direct association with IgG responses (ρ = 0.44,
< 0.05) in HIV- but did not show any association in PWH. Similar associations between age, IgG, and HIV status emerged at day 14 (T1; ρ = 0.50,
< 0.05), 3 months (T3; ρ = 0.50,
< 0.05), and 6 months visit (T4; ρ = 0.78,
< 0.05) in the HIV- group.
The Ab responses in the 6-month post-SARS-CoV-2 infection did not differ by HIV status, though a positive association was found between age and Ab response in older PWH. Results suggest that immune protection and vaccine responses are similar for PWH than for those without HIV infection.
Atorvastatin is a commonly used oral cholesterol-lowering agent. Side effects associated with statin therapy include arthralgia, myalgia, dyspepsia, weakness, and headache. Prospective and ...retrospective studies of drug-induced liver injury have identified statin-induced hepatotoxicity, with atorvastatin being the most commonly cited. Associated liver function test elevations have varied from hepatocellular to cholestatic/mixed pattern. We report a case of a 58-year-old woman that illustrates unusual histologic findings associated with a mixed pattern of statin-induced liver injury. While being treated with atorvastatin, the patient exhibited repeated bouts of abdominal pain over a year associated with biliary tree dilation, variably attributed to postcholecystectomy dilation and stenosis of the ampulla of Vater. Following sphincterotomy, the patient’s bilirubin normalized but the other liver function tests remained elevated. Liver biopsy revealed portal and lobular inflammation with cholangiolysis. The patient’s liver function tests normalized following cessation of atorvastatin therapy.
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