Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes.

Functional reactivation of p53 pathway, although arduous, can potentially provide a broad-based strategy for cancer therapy owing to frequent p53 inactivation in human cancer. Using a phosphoprotein-screening array, we found that Benzyl Isothiocynate, (BITC) increases p53 phosphorylation in breast cancer cells and reveal an important role of ERK and PRAS40/MDM2 in BITC-mediated p53 activation. We show that BITC rescues and activates p53-signaling network and inhibits growth of p53-mutant cells. Mechanistically, BITC induces p73 expression in p53-mutant cells, disrupts the interaction of p73 and mutant-p53, thereby releasing p73 from sequestration and allowing it to be transcriptionally active. Furthermore, BITC-induced p53 and p73 axes converge on tumor-suppressor LKB1 which is transcriptionally upregulated by p53 and p73 in p53-wild-type and p53-mutant cells respectively; and in a feed-forward mechanism, LKB1 tethers with p53 and p73 to get recruited to p53-responsive promoters. Analyses of BITC-treated xenografts using LKB1-null cells corroborate in vitro mechanistic findings and establish LKB1 as the key node whereby BITC potentiates as well as rescues p53-pathway in p53-wild-type as well as p53-mutant cells. These data provide first in vitro and in vivo evidence of the integral role of previously unrecognized crosstalk between BITC, p53/LKB1 and p73/LKB1 axes in breast tumor growth-inhibition

Field-induced quantum fluctuations in the heavy fermion superconductor CeCu2Ge2

Quantum-mechanical fluctuations in strongly correlated electron systems cause unconventional phenomena such as non-Fermi liquid behavior, and arguably high temperature superconductivity. Here we report the discovery of a field-tuned quantum critical phenomenon in stoichiometric CeCu2Ge2, a spin density wave ordered heavy fermion metal that exhibits unconventional superconductivity under ~ 10 GPa of applied pressure. Our finding of the associated quantum critical spin fluctuations of the antiferromagnetic spin density wave order, dominating the local fluctuations due to single-site Kondo effect, provide new information about the underlying mechanism that can be important in understanding superconductivity in this novel compound.Comment: Heavy Fermion, Quantum Critical Phenomeno

Can cancer patients assess the influence of pain on functions? A randomised, controlled study of the pain interference items in the Brief Pain Inventory

BACKGROUND: The Brief Pain Inventory (BPI) is recommended as a pain measurement tool by the Expert Working Group of the European Association of Palliative Care. The BPI is designed to assess both pain severity and interference with functions caused by pain. The purpose of this study was to investigate if pain interference items are influenced by other factors than pain. METHODS: We asked adult cancer patients to complete the original and a revised BPI on two study days. In the original version of the BPI the patients were asked how, during the last 24 hours, pain has interfered with functions. In the revised BPI this question was changed to how, during the last 24 hours, these functions are affected in general. Heath related quality of life was assessed at both study days applying the European Organization for Research and Treatment of Cancer quality of life questionnaire. RESULTS: Forty-eight of the 55 included patients completed both assessments. The BPI pain intensities scores and the health related quality of life scores were similar at the two study days. Except for mood this study observed no significant distinctions between the patients' BPI interference items scores in the original (pain influence on function) and the revised BPI (function in general). Seventeen patients reported higher influence from pain on functions than the total influence on function from all causes. CONCLUSION: We observed similar scores in the original BPI interference scores (pain influence on function) compared with the revised BPI interference scores (decreased function in general). This finding might imply that the BPI interference scale measures are partly responded to as more of a global interference measure

Enhancer, transcriptional, and cell fate plasticity precedes intestinal determination during endoderm development

After acquiring competence for selected cell fates, embryonic primordia may remain plastic for variable periods before tissue identity is irrevocably determined (commitment). We investigated the chromatin basis for these developmental milestones in mouse endoderm, a tissue with recognizable rostro-caudal patterning and transcription factor (TF)-dependent interim plasticity. Foregut-specific enhancers are as accessible and active in early midgut as in foregut endoderm, and intestinal enhancers and identity are established only after ectopic cis-regulatory elements are decommissioned. Depletion of the intestinal TF CDX2 before this cis element transition stabilizes foregut enhancers, reinforces ectopic transcriptional programs, and hence imposes foregut identities on the midgut. Later in development, as the window of chromatin plasticity elapses, CDX2 depletion weakens intestinal, without strengthening foregut, enhancers. Thus, midgut endoderm is primed for heterologous cell fates, and TFs act on a background of shifting chromatin access to determine intestinal at the expense of foregut identity. Similar principles likely govern other fate commitments

Quantum Criticality in Heavy Fermion Metals

Quantum criticality describes the collective fluctuations of matter undergoing a second-order phase transition at zero temperature. Heavy fermion metals have in recent years emerged as prototypical systems to study quantum critical points. There have been considerable efforts, both experimental and theoretical, which use these magnetic systems to address problems that are central to the broad understanding of strongly correlated quantum matter. Here, we summarize some of the basic issues, including i) the extent to which the quantum criticality in heavy fermion metals goes beyond the standard theory of order-parameter fluctuations, ii) the nature of the Kondo effect in the quantum critical regime, iii) the non-Fermi liquid phenomena that accompany quantum criticality, and iv) the interplay between quantum criticality and unconventional superconductivity.Comment: (v2) 39 pages, 8 figures; shortened per the editorial mandate; to appear in Nature Physics. (v1) 43 pages, 8 figures; Non-technical review article, intended for general readers; the discussion part contains more specialized topic

A study protocol of a randomised controlled trial incorporating a health economic analysis to investigate if additional allied health services for rehabilitation reduce length of stay without compromising patient outcomes

Background Reducing patient length of stay is a high priority for health service providers. Preliminary information suggests additional Saturday rehabilitation services could reduce the time a patient stays in hospital by three days. This large trial will examine if providing additional physiotherapy and occupational therapy services on a Saturday reduces health care costs, and improves the health of hospital inpatients receiving rehabilitation compared to the usual Monday to Friday service. We will also investigate the cost effectiveness and patient outcomes of such a service. Methods/Design A randomised controlled trial will evaluate the effect of providing additional physiotherapy and occupational therapy for rehabilitation. Seven hundred and twelve patients receiving inpatient rehabilitation at two metropolitan sites will be randomly allocated to the intervention group or control group. The control group will receive usual care physiotherapy and occupational therapy from Monday to Friday while the intervention group will receive the same amount of rehabilitation as the control group Monday to Friday plus a full physiotherapy and occupational therapy service on Saturday. The primary outcomes will be patient length of stay, quality of life (EuroQol questionnaire), the Functional Independence Measure (FIM), and health utilization and cost data. Secondary outcomes will assess clinical outcomes relevant to the goals of therapy: the 10 metre walk test, the timed up and go test, the Personal Care Participation Assessment and Resource Tool (PC PART), and the modified motor assessment scale. Blinded assessors will assess outcomes at admission and discharge, and follow up data on quality of life, function and health care costs will be collected at 6 and 12 months after discharge. Between group differences will be analysed with analysis of covariance using baseline measures as the covariate. A health economic analysis will be carried out alongside the randomised controlled trial. Discussion This paper outlines the study protocol for the first fully powered randomised controlled trial incorporating a health economic analysis to establish if additional Saturday allied health services for rehabilitation inpatients reduces length of stay without compromising discharge outcomes. If successful, this trial will have substantial health benefits for the patients and for organizations delivering rehabilitation services

Leptin and Adiponectin: new players in the field of tumor cell and leukocyte migration

Adipose tissue is no longer considered to be solely an energy storage, but exerts important endocrine functions, which are primarily mediated by a network of various soluble factors derived from fat cells, called adipocytokines. In addition to their responsibility to influence energy homeostasis, new studies have identified important pathways linking metabolism with the immune system, and demonstrating a modulatory role of adipocytokines in immune function. Additionally, epidemiological studies underline that obesity represents a significant risk factor for the development of cancer, although the exact mechanism of this relationship remains to be determined. Whereas a possible influence of adipocytokines on the proliferation of tumor cells is already known, new evidence has come to light elucidating a modulatory role of this signaling substances in the regulation of migration of leukocytes and tumor cells. The migration of leukocytes is a key feature to fight cancer cells, whereas the locomotion of tumor cells is a prerequisite for tumor formation and metastasis. We herein review the latest tumor biological findings on the role of the most prominent adipocytokines leptin and adiponectin, which are secreted by fat cells, and which are involved in leukocyte migration, tumor growth, invasion and metastasis. This review thus accentuates the complex, interactive involvement of adipocytokines in the regulation of migration of both leukocytes and tumor cells, and gives an insight in the underlying molecular mechanisms

Leptin Activates Human B Cells to Secrete TNF-α, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 Signaling Pathway

Leptin, one of the adipokines, functions as a hormone and a cytokine. In this investigation, we show for the first time that leptin, in a concentration-dependent manner, activates human peripheral blood B cells to induce secretion of IL-6, IL-10, and TNF-α. Leptin increased B cells expressing CD25 and HLA-DR. Leptin induces phosphorylation of Janus activation kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), p38 mitogen-activated protein kinase (p38MAPK), and extracellular signal-regulated kinase (ERK1/2). Furthermore, leptin-induced cytokine secretion by B cells was blocked by inhibitors of JAK2, STAT3, p38MAPK, and ERK1/2. These data demonstrate that leptin activates human B cells to secrete cytokines via activation of JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathways, which may contribute to its inflammatory and immunoregulatory properties

Total and High Molecular Weight Adiponectin and Hepatocellular Carcinoma with HCV Infection

Adiponectin is shown to be inversely associated with development and progression of various cancers. We evaluated whether adiponectin level was associated with the prevalence and histological grade of hepatocellular carcinoma (HCC), and liver fibrosis in patients with hepatitis C virus (HCV) infection.A case-control study was conducted on 97 HCC patients (cases) and 97 patients (controls) matched for sex, Child-Pugh grade and platelet count in patients with HCV infection. The serum total and high molecular weight (HMW) adiponectin levels were measured by enzyme-linked immunosorbent assays and examined in their association with the prevalence of HCC. In addition, the relationship between these adiponectin levels and body mass index (BMI), progression of liver fibrosis, and histological grade of HCC was also evaluated. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI).There were no significant differences in the serum total and HMW adiponectin levels between cases and controls. Moreover, there were no inverse associations between serum total and HMW adiponectin levels and BMI in both cases and controls. On the other hand, serum total and HMW adiponectin levels are positively correlated with APRI in both cases (r = 0.491, P<0.001 and r = 0.485, P<0.001, respectively) and controls (r = 0.482, P<0.001 and r = 0.476, P<0.001, respectively). Interestingly, lower serum total (OR 11.76, 95% CI: 2.97–46.66 [P<0.001]) and HMW (OR 10.24, CI: 2.80–37.40 [P<0.001] adiponectin levels were independent risk factors of worse histological grade of HCC.Our results suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low these adiponectin levels were significantly associated with worse histological grades