MAP2K4/MKK4 expression in pancreatic cancer: genetic validation of immunohistochemistry and relationship to disease course.

MKK4 (MAP2K4/SEK1) is a member of the mitogen-activated protein kinase family, originally identified as a kinase involved in the stress-activated protein kinase pathway by directly phosphorylating c-Jun NH2-terminal kinase. MKK4 genetic inactivation has been observed in a subset of pancreatic carcinomas, implicating deregulation of the stress-activated protein kinase pathway in pancreatic carcinogenesis. We evaluated Mkk4 protein expression patterns by immunohistochemical labeling in a series of 60 resected primary infiltrating pancreatic adenocarcinomas (24 cases with known MKK4 genetic status), and 14 different tissue arrays representing the primary carcinoma and all of the gross metastases from 26 patients that died of metastatic pancreatic cancer. Among the surgically resected carcinomas, focal or diffuse-positive immunolabeling for Mkk4 protein was found in 52 of 60 cases (86.7%). Among the eight carcinomas with negative Mkk4 immunolabeling, three harbored a homozygous deletion or intragenic mutation of the MKK4 gene, in contrast to none of the 52 cases with positive Mkk4 immunolabeling (P < 0.01). Loss of Mkk4 immunolabeling showed a trend toward shorter survival, with Mkk4-positive carcinomas having half the risk of death than Mkk4-negative carcinomas (P = 0.09). Mkk4 immunolabeling patterns were also evaluated among unresectable primary and metastatic cancer tissues from autopsy specimens, indicating intact Mkk4 immunolabeling in 88.8% of the unresectable primary carcinomas as compared with 63.3% of distant metastases (P < 0.001). Our data indicate that the loss of Mkk4 protein expression in pancreatic carcinomas may be more frequent than suggested by the rates of genetic inactivation alone and that MKK4 loss may contribute to disease progression. The correlation of MKK4 genetic status with immunolabeling patterns validate this approach for the evaluation of MKK4 status in routine histologic sections and may provide useful information regarding patient prognosis.     

Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes.

PURPOSE: Nemorubicin (3'-deamino-3'-[2'(S)-methoxy-4'-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3',4'-anhydro-[2'(S)-methoxy-3'(R)-oxy-4'-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682. EXPERIMENTAL DESIGN: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively. RESULTS: HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts. CONCLUSIONS: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.     

Vitamin-D Deficiency and Supplementation Altered the Network of the Coronary Arteries in a Rodent Model—In Situ Video Microscopic Technique

The aim of our study was to identify whether vitamin-D deficiency (VDD) can alter the geometry of the coronary-resistance-artery system. Male Wistar rats were divided into vitamin-D-deficient (VD−, n = 10) and vitamin-D-supplemented (VD+, n = 8) groups. After eight weeks, branches and segments of the left-anterior-descending-coronary-artery (LAD) network were analyzed by a video-microscopy technique. Segments were divided into 50 μm-long cylindrical ring units. VDD did not increase the number of morphological abnormalities. The number of segments did not differ between the groups (VD−: 210 and VD+: 224; pooled data of 8 networks). A larger lumen area of branches was found in VD+ group, while 1–4-order branches were lengthier in the VD− group. VD− rats had less rich coronary-resistance-artery networks in terms of 50 µm-long units. (VD−: 6365 vs. VD+: 6602; pooled data of 8 networks). VD+ animals were richer in the 100–350 µm outer diameter range, and VD− animals were richer in the 400–550 µm-diameter units. In VD− rats, 150–200 and 300 µm units were almost missing at higher flow distances from the orifice. Serum vitamin-D alterations caused by dietary changes can affect the geometry of the coronary-artery network, which may contribute to vitamin-D-dependent changes in cardiovascular mortality.     

Discal cyst: a rare cause of low back pain and sciatica

We report a case of a 54-year-old man suffering from sciatalgia unresponsive to medical treatment. Imaging revealed a discal cyst the level L3-L4, a rare cause of low back pain, which has characteristic imaging features. In particular, on Magnetic Resonance Imaging it appears as a cystic formation with fluid content, which usually arises from the posterior contour of the intervertebral disc and it frequently has air bubbles within it. The patient underwent surgical treatment with resolution of symptoms.     

Behavioural insights and the evolving COVID-19 pandemic

Behavioural sciences have complemented medical and epidemiological sciences in the response to the SARS-CoV-2 pandemic. As vaccination uptake continues to increase across the EU/EEA – including booster vaccinations – behavioural science research remains important for both pandemic policy, planning of services and communication. From a behavioural perspective, the following three areas are key as the pandemic progresses: (i) attaining and maintaining high levels of vaccination including booster doses across all groups in society, including socially vulnerable populations, (ii) informing sustainable pandemic policies and ensuring adherence to basic prevention measures to protect the most vulnerable population, and (iii) facilitating population preparedness and willingness to support and adhere to the reimposition of restrictions locally or regionally whenever outbreaks may occur. Based on mixed-methods research, expert consultations, and engagement with communities, behavioural data and interventions can thus be important to prevent and effectively respond to local or regional outbreaks, and to minimise socioeconomic and health disparities. In this Perspective, we briefly outline these topics from a European viewpoint, while recognising the importance of considering the specific context in individual countries.     

Randomized Clinical Trial of Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Sleeve Gastrectomy for the Management of Patients with BMI < 50 kg/m<Superscript>2</Superscript>

Background  

Laparoscopic Roux-en-Y gastric bypass (LRYGB) is currently the gold standard bariatric procedure for the treatment of morbid obesity. Laparoscopic sleeve gastrectomy (LSG) is a relatively innovative procedure which has been increasingly applied lately as a sole bariatric procedure. A randomized trial was conducted in a Greek population to evaluate perioperative safety and 3-years results.