Effect of atorvastatin on skeletal muscles of patients with knee osteoarthritis: Post-hoc analysis of a randomised controlled trial

PUBLISHED 25 August 2022Objective: Populations with knee osteoarthritis (KOA) are at increased risk of cardiovascular disease, due to higher prevalence of risk factors including dyslipidaemia, where statins are commonly prescribed. However, the effect of statins on muscles and symptoms in this population is unknown. Thus, this study examined the effect of atorvastatin on muscle properties in patients with symptomatic KOA. Design: Post-hoc analysis of a 2-year multicentre randomised, double-blind, placebo-controlled trial. Setting: Australian community. Participants: Participants aged 40–70 years (mean age 55.7 years, 55.6% female) with KOA who met the American College of Rheumatology clinical criteria received atorvastatin 40 mg daily (n = 151) or placebo (n = 153). Main outcome measures: Levels of creatinine kinase (CK), aspartate transaminase (AST), and alanine transaminase (ALT) at 1, 6, 12, and 24 months; muscle strength (by dynamometry) at 12 and 24 months; vastus medialis cross-sectional area (CSA) on magnetic resonance imaging at 24 months; and self-reported myalgia. Results: There were no significant between-group differences in CK and AST at all timespoints. The atorvastatin group had higher ALT than placebo group at 1 (median 26 vs. 21, p = 0.004) and 6 (25 vs. 22, p = 0.007) months without significant between-group differences at 12 and 24 months. Muscle strength increased in both groups at 24 months without between-group differences [mean 8.2 (95% CI 3.5, 12.9) vs. 5.9 (1.3, 10.4), p = 0.49]. Change in vastus medialis CSA at 24 months favoured the atorvastatin group [0.11 (−0.10, 0.31) vs. −0.23 (−0.43, −0.03), p = 0.02] but of uncertain clinical significance. There was a trend for more myalgia in the atorvastatin group (8/151 vs. 2/153, p = 0.06) over 2 years, mostly occurring within 6 months (7/151 vs. 1/153, p = 0.04). Conclusions: In those with symptomatic KOA, despite a trend for more myalgia, there was no clear evidence of an adverse effect of atorvastatin on muscles, including those most relevant to knee joint health.Yuan Z. Lim, Flavia M. Cicuttini, Anita E. Wluka, Graeme Jones, Catherine L. Hill, Andrew B. Forbes, Andrew Tonkin, Sofia Berezovskaya, Lynn Tan, Changhai Ding and Yuanyuan Wan

High Smac/DIABLO expression is associated with early local recurrence of cervical cancer

<p>Abstract</p> <p>Background</p> <p>In a recent pilot report, we showed that Smac/DIABLO mRNA is expressed <it>de novo </it>in a subset of cervical cancer patients. We have now expanded this study and analyzed Smac/DIABLO expression in the primary lesions in 109 cervical cancer patients.</p> <p>Methods</p> <p>We used immunohistochemistry of formalin-fixed, paraffin-embedded tissue sections to analyze Smac/DIABLO expression in the 109 primary lesions. Seventy-eight samples corresponded to epidermoid cervical cancer and 31 to cervical adenocarcinoma. The median follow up was 46.86 months (range 10–186).</p> <p>Results</p> <p>Smac/DIABLO was expressed in more adenocarcinoma samples than squamous tumours (71% vs 50%; p = 0.037). Among the pathological variables, a positive correlation was found between Smac/DIABLO immunoreactivity and microvascular density, a marker for angiogenesis (p = 0.04). Most importantly, Smac/DIABLO immunoreactivity was associated with a higher rate of local recurrence in squamous cell carcinoma (p = 0.002, log rank test). No association was found between Smac/DIABLO and survival rates.</p> <p>Conclusion</p> <p>Smac/DIABLO expression is a potential marker for local recurrence in cervical squamous cell carcinoma patients.</p

Результаты лучевой терапии в сочетании с капецитабином и оксалиплатином в лечении больных плоскоклеточным раком анального канала: непосредственные и отдаленные результаты

Introduction. The current standard of care is concurrent radiation therapy (RT) and chemotherapy with mitomycin or cisplatin in combination with fuoropyrimidine drugs. One possible option for effective chemotherapy regimens with a lower toxicity is the combination of oxaliplatin and capecitabine with RT. The purpose of the study: a retrospective evaluation of the results of combined treatment of 74 patients with squamous cell carcinoma of the anus (SCCA) with the use of oxaliplatin and capecitabine. Material and Methods. The study included 74 patients (men – 12.2 %, women – 87.8 %) with stage I–III SCCA. All patients underwent megavolt photon RT (2×25), a cumulative dose of 50 Gy and a boost of 10 Gy to the anal canal. From days 1 to 14 and from days 22 to 36 of RT, capecitabine was administered orally at a dose of 825 mg/m2  twice a day in combination with intravenous administration of oxaliplatin 50 mg/m2  on days 1, 8, 22, and 29 of RT. If a residual tumor 6 months after completion of chemoradiotherapy was found, patients underwent surgery. Results. All 74 patients underwent RT with a cumulative dose of 60 Gy. Chemotherapy, according to the protocol, was completed in 58 (78.4 %) patients. Grade 3-4 toxicity was noted in 11 (14.9 %) patients. In 64 patients (86.5 %), a complete clinical response was registered. At least one late radiation side effects according to the RTOG (LENT SOMA) scale was noted in 48 (98.0 %) patients, including grade 3-4 complications in 12 (24.5 %) patients. With a median follow-up of 40 months (3-82) cumulative three-year local recurrence rate, overall and relapse-free survival were 15.3 ± 4.5 %, 73.7 ± 5.7 % and 53.5 ± 6.4 %, respectively. Conclusion. Combined treatment of SCCA, based on the combination of RT with chemotherapy with oxaliplatin and capecitabine, is feasible and has acceptable acute toxicity. Additional clinical studies are needed using this chemotherapy regimen in combination with modern RT techniques.Введение. Плоскоклеточный рак анального канала (ПРАК) является редкой локализацией в структуре заболеваемости злокачественными новообразованиями во всем мире. Современным стандартом лечения ПРАК является сочетание лучевой терапии (ЛТ) с химиотерапией митомицином или цисплатином с препаратами фторпиримидинового ряда. Один из эффективных лекарственных режимов с меньшим профилем токсичности – сочетание оксалиплатина и капецитабина в комбинации с ЛТ. Цель исследования – ретроспективная оценка результатов комбинированного лечения 74 пациентов с ПРАК с использованием препаратов оксалиплатин и капецитабин. Методы. В исследование включены 74 пациента (мужчины – 12,2 %, женщины – 87,8 %) с ПРАК I–III стадии. Всем больным проводили мегавольтную конвенциональную ЛТ до СОД 50 Гр (2×25) и бустом 10 Гр на зону анального канала. С 1 по 14-й и с 22 по 36-й дни облучения назначали пероральный прием капецитабина в дозе 825 мг/м2 дважды в день в сочетании с внутривенным введением оксалиплатина 50 мг/м2  в 1, 8, 22, 29-й дни ЛТ. При наличии остаточной опухоли через 6 мес после завершения ХЛТ выполняли хирургические вмешательства. Результаты. ЛТ во всех случаях завершена в полном объеме, завершенность химиотерапии составила 78,4 % больных. Лучевые реакции отмечены у всех пациентов, однако реакции III–IV степени – у 11 (14,9 %) больных. В группу динамического наблюдения включены 64 (86,5 %) пациента с полным клиническим ответом. Оценка поздних лучевых повреждений по шкале RTOG (LENT SOMA) проведена у 49 пациентов. У 48 (98,0 %) больных было отмечено хотя бы одно лучевое повреждение, в том числе осложнения III–IV степени зарегистрированы у 12 (24,5 %) пациентов. Постлучевые изменения костной ткани отмечены у 19 (38,8 %) пациентов, 7 больным потребовалось эндопротезирование тазобедренных суставов. При медиане наблюдения 40 мес (3–82) кумулятивная 3-летняя частота местных рецидивов, общая и безрецидивная 3-летняя выживаемость составили 15,3 ± 4,5; 73,7 ± 5,7 и 53,5 ± 6,4 % соответственно, Заключение. Комбинированное лечение ПРАК, основанное на сочетании ЛТ с химиотерапией препаратами оксалиплатин и капецитабин, удовлетворительно переносится пациентами. Необходимы дополнительные клинические исследования с использованием данного режима химиотерапии в сочетании с современными методиками ЛТ

Invading Basement Membrane Matrix Is Sufficient for MDA-MB-231 Breast Cancer Cells to Develop a Stable In Vivo Metastatic Phenotype

1 - ArticleIntroduction: The poor efficacy of various anti-cancer treatments against metastatic cells has focused attention on the role of tumor microenvironment in cancer progression. To understand the contribution of the extracellular matrix (ECM) environment to this phenomenon, we isolated ECM surrogate invading cell populations from MDA-MB-231 breast cancer cells and studied their genotype and malignant phenotype. Methods: We isolated invasive subpopulations (INV) from non invasive populations (REF) using a 2D-Matrigel assay, a surrogate of basal membrane passage. INV and REF populations were investigated by microarray assay and for their capacities to adhere, invade and transmigrate in vitro, and to form metastases in nude mice. Results: REF and INV subpopulations were stable in culture and present different transcriptome profiles. INV cells were characterized by reduced expression of cell adhesion and cell-cell junction genes (44% of down regulated genes) and by a gain in expression of anti-apoptotic and pro-angiogenic gene sets. In line with this observation, in vitro INV cells showed reduced adhesion and increased motility through endothelial monolayers and fibronectin. When injected into the circulation, INV cells induced metastases formation, and reduced injected mice survival by up to 80% as compared to REF cells. In nude mice, INV xenografts grew rapidly inducing vessel formation and displaying resistance to apoptosis. Conclusion: Our findings reveal that the in vitro ECM microenvironment per se was sufficient to select for tumor cells with a stable metastatic phenotype in vivo characterized by loss of adhesion molecules expression and induction of proangiogenic and survival factors

Comparative web search questions

We analyze comparative questions, i.e., questions asking to compare different items, that were submitted to Yandex in 2012. Responses to such questions might be quite different from the simple “ten blue links” and could, for example, aggregate pros and cons of the different options as direct answers. However, changing the result presentation is an intricate decision such that the classification of comparative questions forms a highly precision-oriented task. From a year-long Yandex log, we annotate a random sample of 50,000 questions; 2.8% of which are comparative. For these annotated questions, we develop a precision-oriented classifier by combining carefully hand-crafted lexico-syntactic rules with feature-based and neural approaches—achieving a recall of 0.6 at a perfect precision of 1.0. After running the classifier on the full year log (on average, there is at least one comparative question per second), we analyze 6,250 comparative questions using more fine-grained subclasses (e.g., should the answer be a “simple” fact or rather a more verbose argument) for which individual classifiers are trained. An important insight is that more than 65% of the comparative questions demand argumentation and opinions, i.e., reliable direct answers to comparative questions require more than the facts from a search engine’s knowledge graph. In addition, we present a qualitative analysis of the underlying comparative information needs (separated into 14 categories like consumer electronics or health), their seasonal dynamics, and possible answers from community question answering platforms. © 2020 Copyright held by the owner/author(s).This work has been partially supported by the DFG through the project “ACQuA: Answering Comparative Questions with Arguments” (grants BI 1544/7-1 and HA 5851/2-1) as part of the priority program “RATIO: Robust Argumentation Machines” (SPP 1999). We thank Yandex and Mail.Ru for granting access to the data. The study was partially conducted during Pavel Braslavski’s research stay at the Bauhaus-Universität Weimar in 2018 supported by the DAAD. We also thank Ekaterina Shirshakova and Valentin Dittmar for their help in question annotation

Ex Vivo Expansion of Human CD8+ T Cells Using Autologous CD4+ T Cell Help

Background: Using in vivo mouse models, the mechanisms of CD4+ T cell help have been intensively investigated. However, a mechanistic analysis of human CD4+ T cell help is largely lacking. Our goal was to elucidate the mechanisms of human CD4+ T cell help of CD8+ T cell proliferation using a novel in vitro model. Methods/Principal Findings: We developed a genetically engineered novel human cell-based artificial APC, aAPC/mOKT3, which expresses a membranous form of the anti-CD3 monoclonal antibody OKT3 as well as other immune accessory molecules. Without requiring the addition of allogeneic feeder cells, aAPC/mOKT3 enabled the expansion of both peripheral and tumor-infiltrating T cells, regardless of HLA-restriction. Stimulation with aAPC/mOKT3 did not expand Foxp3+ regulatory T cells, and expanded tumor infiltrating lymphocytes predominantly secreted Th1-type cytokines, interferon-γ and IL-2. In this aAPC-based system, the presence of autologous CD4+ T cells was associated with significantly improved CD8+ T cell expansion in vitro. The CD4+ T cell derived cytokines IL-2 and IL-21 were necessary but not sufficient for this effect. However, CD4+ T cell help of CD8+ T cell proliferation was partially recapitulated by both adding IL-2/IL-21 and by upregulation of IL-21 receptor on CD8+ T cells. Conclusions: We have developed an in vitro model that advances our understanding of the immunobiology of human CD4+ T cell help of CD8+ T cells. Our data suggests that human CD4+ T cell help can be leveraged to expand CD8+ T cells in vitro

Cord Blood Stem Cell-Mediated Induction of Apoptosis in Glioma Downregulates X-Linked Inhibitor of Apoptosis Protein (XIAP)

XIAP (X-linked inhibitor of apoptosis protein) is one of the most important members of the apoptosis inhibitor family. XIAP is upregulated in various malignancies, including human glioblastoma. It promotes invasion, metastasis, growth and survival of malignant cells. We hypothesized that downregulation of XIAP by human umbilical cord blood mesenchymal stem cells (hUCBSC) in glioma cells would cause them to undergo apoptotic death.We observed the effect of hUCBSC on two malignant glioma cell lines (SNB19 and U251) and two glioma xenograft cell lines (4910 and 5310). In co-cultures of glioma cells with hUCBSC, proliferation of glioma cells was significantly inhibited. This is associated with increased cytotoxicity of glioma cells, which led to glioma cell death. Stem cells induced apoptosis in glioma cells, which was evaluated by TUNEL assay, FACS analyses and immunoblotting. The induction of apoptosis is associated with inhibition of XIAP in co-cultures of hUCBSC. Similar results were obtained by the treatment of glioma cells with shRNA to downregulate XIAP (siXIAP). Downregulation of XIAP resulted in activation of caspase-3 and caspase-9 to trigger apoptosis in glioma cells. Apoptosis is characterized by the loss of mitochondrial membrane potential and upregulation of mitochondrial apoptotic proteins Bax and Bad. Cell death of glioma cells was marked by downregulation of Akt and phospho-Akt molecules. We observed similar results under in vivo conditions in U251- and 5310-injected nude mice brains, which were treated with hUCBSC. Under in vivo conditions, Smac/DIABLO was found to be colocalized in the nucleus, showing that hUCBSC induced apoptosis is mediated by inhibition of XIAP and activation of Smac/DIABLO.Our results indicate that downregulation of XIAP by hUCBSC treatment induces apoptosis, which led to the death of the glioma cells and xenograft cells. This study demonstrates the therapeutic potential of XIAP and hUCBSC to treat malignant gliomas

Trophic macrophages in development and disease

Specialized phagocytes are found in the most primitive multicellular organisms. Their roles in homeostasis and in distinguishing self from non-self have evolved with the complexity of organisms and their immune systems. Equally important, but often overlooked, are the roles of macrophages in tissue development. As discussed in this Review, these include functions in branching morphogenesis, neuronal patterning, angiogenesis, bone morphogenesis and the generation of adipose tissue. In each case, macrophage depletion impairs the formation of the tissue and compromises its function. I argue that in several diseases, the unrestrained acquisition of these developmental macrophage functions exacerbates pathology. For example, macrophages enhance tumour progression and metastasis by affecting tumour-cell migration and invasion, as well as angiogenesis