Correction to: A phase I study of LY3164530, a bispecific antibody targeting MET and EGFR, in patients with advanced or metastatic cancer

The original version of this article unfortunately contained a mistake. The co-authors' names were incorrect.

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Multiple lesions of skull and cervical spine: a rare presentation of unicameral bone cysts

A 55-year-old man with a history of Benign Paroxysmal Positional Vertigo unalleviated by Epley manoeuvre presented to an otolaryngologist for dizziness, right ear fullness and headache. MRI of the brain showed numerous marrow-replacing lesions throughout the calvarium, skull base and upper cervical spine which were hypointense on T1-weighted images, hyperintense on T2-weighted images and avidly enhanced following contrast, concerning for a malignant process such as metastatic disease or multiple myeloma (figure 1). Systemic X-ray survey (spine, skull, chest, pelvis, all long bones) and nuclear medicine whole body bone scan were negative except for the lesions seen on MRI. β–2microglobin, immunoglobin and monoclonal protein electrophoresis were negative for myeloma or immunological process. Given the concern for metastatic disease, biopsy of a skull lesion was recommended. Pathological analysis of a calvarial lesion was consistent with unicameral bone cyst (figure 1). No ongoing therapy was offered; however, brain and spine surveillance imaging will continue.

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Orbitocerebral mucormycosis and intracranial haemorrhage: a role for caution with steroids in suspected giant cell arteritis

A 75-year-old man with type 2 diabetes mellitus presented with complete loss of vision in his right eye and severe headaches for the past 24 hours. He had been treated for suspected giant cell arteritis (GCA) with high-dose corticosteroids which were being tapered to stop after an inconclusive right temporal artery biopsy and an erythrocyte sedimentation rate (ESR) value of 8. His current acute presentation, however, raised further concern for partially treated GCA and precipitated treatment with pulsed methylprednisolone. The patient, taking metformin, developed diabetic ketoacidosis and was transferred to the intensive care unit where a swollen, painful right eye with chemosis and complete ophthalmoplegia was subsequently revealed to be secondary to cavernous sinus thrombosis. Rhino-orbital skin necrosis with positive samples for the organism Rhizopus on eventual orbital exenteration revealed angioinvasive fungal infection, mucormycosis, to be the cause. We discuss here the lessons learnt, and how best to treat a susceptible cohort within our ageing western population.

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Spontaneous migration into the stomach and out of the intestine, as late complication of a gastric band

Description 

A 45-year-old woman with morbid obesity (body mass index 44 kg/m²) presented to the emergency department with severe abdominal pain, nausea, vomiting and no defaecation. She had a laparoscopic adjustable gastric banding (LAGB) inserted elsewhere in 2006. No data or follow-up was performed postoperatively. A CT scan demonstrated a perforated LAGB through the gastric antrum (figure 1). Furthermore the connecting tube perforated the small intestine at the level of the proximal part of the jejunum with a partially intraluminally positioned banding (figure 2), causing prestenotic dilatation of the jejunum (figure 3). An upper gastrointestinal endoscopy confirmed an intact port site with a connected tube and migration and perforation of the band into the jejunum with an erosion of the gastric (figure 4) and duodenal wall. At closer inspection of the port site and connecting tube, we observed a high level...

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Emphysematous Osteomyelitis

Description

A 56-year-old man with a known history of type 2 diabetes mellitus, hypertension, nephrolithiasis and gout presented with fatigue and flank pain for 3 days. The above symptoms were associated with fevers and chills. On admission, the patient's vitals were remarkable for fever with maximum temperature (T max) 39.1°C, hypotension requiring pressor support and tachycardia. On auscultation, he had reduced air entry at lung bases, distended abdomen, bipedal oedema and petechial rash over the upper extremities and the trunks. In addition, there was purplish discolouration over the left medial sacral area. Laboratory work-up was remarkable for elevated white cell count 21.4x10⁹/L (4.0–12.0x10⁹/L), creatinine 7.98 mg/dL (0.60–1.40 mg/dL), anion gap of 25, erythrocyte sedimentation rate of 70 mm/hour (0–20 mm/hour), total bilirubin of 4.9 mg/dL (0.2–1.2 mg/dL) and lipase 422 U/L (0–140 U/L). Platelet count was 31x10³/µL (150–400 10³/µL), aspartate aminotransferase of 71 U/L (10–40 U/L) and alanine aminotransferase of 37 U/L (3–45 U/L). Septic shock was suspected, and the patient was...

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Campylobacter fetus spondylodiscitis in a patient with HIV infection and restored CD4 count

Campylobacter fetus (C. fetus) is a rare condition and mostly seen in elderly or immunocompromised patients. We present the first case of C. fetus spondylodiscitis in a virologically suppressed HIV seropositive patient with low back pain. MRI was performed and showed spondylodiscitis of the L4–L5 region. Empirical antibiotic therapy with flucloxacillin was started after blood cultures were drawn and an image-guided disc biopsy was performed. Blood cultures remained negative. The anaerobic culture of the puncture biopsy of the disc revealed presence of C. fetus after which the antibiotic treatment was switched to ceftriaxone. Guided by the susceptibility results, the therapy was switched to ciprofloxacin orally for 6 weeks after which the patient made full clinical, biochemical and radiographic recovery. Since no other immune-deficient conditions were noted, it is important to highlight that patients with HIV infection with restored CD4 counts and complete virological suppression can still be susceptible for infections caused by rare pathogens. Low back pain should raise suspicion for these conditions and should be examined properly.

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Case of fatal familial insomnia caused by a d178n mutation with phenotypic similarity to Hashimotos encephalopathy

Fatal familial insomnia (FFI) is a rare prion disease commonly inherited in an autosomal dominant pattern from a mutation in the PRioN Protein (PRNP) gene. Hashimoto's encephalopathy (HE) is characterised by encephalopathy associated with antithyroid peroxidase (TPO) or antithyroglobulin (Tg) antibodies. These two conditions characteristically have differing clinical presentations with dramatically different clinical course and outcomes. Here, we present a case of FFI mimicking HE. A woman in her 50s presented with worsening confusion, hallucinations, tremor and leg jerks. Several maternal relatives had been diagnosed with FFI, but the patient had had negative genetic testing for PRNP. MRI of brain, cervical and thoracic spine were unremarkable except for evidence of prior cervical transverse myelitis. Cerebrospinal fluid analysis was normal. Anti-TPO and anti-Tg antibodies were elevated. She was started on steroids for possible HE and showed improvement in symptoms. Following discharge, the results of her PRNP gene test returned positive for variant p.Asp178Asn.

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The treatment of trismus with Ativan: a 3-year-old with difficulty opening her mouth

Description

A 3-year-old healthy girl presented with intermittent spells of difficulty opening her mouth, talking and swallowing.

Episodes began 3 weeks prior without any inciting incident. Initially occurring weekly, episodes were brief and self-resolving, but had begun increasing in frequency. Symptoms were typically worse later in the day. The presenting episode started 36 hours earlier. The child was eating when her jaw unexpectedly clenched tightly, preventing her from chewing, swallowing or opening her mouth. She had no other neurological symptoms. Family denied any new exposures or trauma. She had no other systemic symptoms. Her father had severe blepharospasms in youth that resolved without treatment.

Her mouth was pursed and jaw tightly clenched (figures 1 and 2). She was drooling and appeared unable to swallow secretions or speak, though was whining and appeared frustrated. Temporomandibular joint (TMJ) was non-tender with symmetrical jaw musculature. She had fasciculations over...

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Rare cause of voiding dysfunction in an adult man: urethral diverticulum compressing the anterior urethra

Description 

A 46-year-old man presented to us with lower urinary tract symptoms that include severe voiding symptoms. He had a history of injury to the perineum 3 years back. A smooth cystic swelling was palpable in the perineum in midline. Uroflowmetry was done and was suggestive of poor urinary flow (Q_avg: 2 mL/s and Q_max: 6 mL/s), with significant postvoid residual urine (PVR). A micturating cystourethrogram (MCU) with retrograde urethrography (RUG) was done and was suggestive of an anterior urethral diverticulum, which was compressing the urethra, along with significant PVR (figure 1). The patient was planned for open excision of the urethral diverticulum. A cystourethroscopy was done preoperatively and clearly showed a normal anterior urethra and the opening of the diverticulum on the ventral aspect of the urethra (figure 2). The patient was operated in lithotomy position and a midline perineal incision was done. The diverticulum was dissected free and then excised,...

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Management of nonmetastatic castration-resistant prostate cancer

Purpose of review The widespread use of prostate-specific antigen (PSA) resulted in stage migration of prostate cancer where androgen deprivation therapy (ADT) is administered for biochemical recurrence in patients following primary treatment. A proportion of these patients progress to a disease state termed nonmetastatic castration-resistant prostate cancer (nmCRPC), with a rising PSA despite ADT and without evidence of metastases on conventional imaging. We will review the treatment options in nmCRPC, especially in light of recent trials showing significant improvement in metastasis-free survival with newer agents. Recent findings Historically, nmCRPC patients were followed-up if PSA doubling-time (PSADT) exceeded 10 months. Treatment options for patients with shorter PSADT included hormonal manipulations that often resulted in transient PSA decline. Denosumab was found to delay the onset of bone metastasis but did not impact survival. Recently, phase 3 trials showed that second-generation antiandrogens resulted in a significant delay in metastasis and a trend toward survival improvement in a select group of nmCRPC patients. Summary The importance of reducing mortality and morbidity associated with metastasis has led to the acceptance of new primary endpoints in the design of trials for nmCRPC and might result in widespread approval of new agents for this disease state. Correspondence to Fred Saad, MD, FRCSC, Division of Urology, University of Montreal Hospital Center, CHUM, Pavillon R, 900, rue St-Denis, porte R04-446, Montréal, Québec H2X 0A9, Canada. Tel: +1 514 890 8000; fax: +1 514 412 7620; e-mail: fred.saad@videotron.ca. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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A contemporary review about the management of radiation-induced hemorrhagic cystitis

Purpose of review There are various specific therapeutic intervention available to treat hemorrhagic cystitis, once emergency treatment has been carried out. The lack of prospective studies, because of the relative rarity of this condition, makes it difficult to hierarchize the therapeutic sequence. The present review presents and summarizes the literature published on radiation-induced hemorrhagic cystitis from April 2015, date of a precedent exhaustive review, to March 2018. Recent findings During our period of interest, 13 clinical studies and two new clinical trials protocols were published. Most of the clinical studies were retrospective and presented data about hyperbaric oxygen (HBO) therapy, comforting its place as a well tolerated and effective first-line treatment. Other studies reported the outcomes of treatments with alum, formalin, silver nitrate, fulguration with laser or definitive surgery. Summary Although authors seem to agree that formalin and surgery have their role as effective but potentially morbid last-line treatments, there is no consensus on primary approach to management of radiation-induced hemorrhagic cystitis beyond symptomatic measures. Several treatments have proven excellent response rates and few side effects. The results of on-going prospective studies on mesenchymal stromal cells or tacrolimus instillations are awaited, but the main discriminating factor to choose between treatments remains local availability. Correspondence to Guila Delouya, Centre hospitalier de l'Université de Montréal (CHUM), 1055, rue Sanguinet, Radio-oncologie, Pavillon C, porte C.S3.5002, Montréal (Québec) H2X 3E4. Tel: +1 514 890 8254; fax: +1 514 412 7537; e-mail: guila.delouya.chum@ssss.gouv.qc.ca Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Treatment of hormone-naïve metastatic prostate cancer

Purpose of review Until 2015, androgen deprivation therapy (ADT) alone was the standard-of-care for metastatic hormone-naïve prostate cancer (mHNPC). In the last decade, important landmark therapeutic advances occurred in the management of these patients permitting improvement of their survival. Recent findings At least two prospective randomized trials proved upfront docetaxel (DOC) + ADT benefit consequently providing strong evidence for guidelines modifications. Second, similar benefit results were demonstrated when using upfront abiraterone acetate + ADT in mHNPC. Summary Both DOC-based chemotherapy and abiraterone acetate provide survival improvement when added to ADT in mHNPC. In the current article, we review the evidence behind this progress and discuss ongoing clinical controversies. Correspondance to Zineb Hamilou, MD, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. Tel: +1 514 890 8000x20696; e-mail: z.hamilou@gmail.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Myofascial pain: so common, and yet not understood

No abstract available

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Psychological support for patients with cancer: evidence review and suggestions for future directions

Purpose of review Psychological distress and mental health comorbidity are common in cancer. Various therapeutic frameworks have been used for interventions to improve psychological wellbeing and quality of life in cancer patients with mixed results. This article reviews contributions to that literature published since January 2017. Recent findings The majority of new psychological intervention research in cancer has used cognitive behavioural therapy (CBT) or mindfulness-based interventions. CBT has been considered a gold-standard intervention and recent evidence justifies continuation of this. Recent reviews call into question the validity of evidence for mindfulness-based interventions. A smaller number of trials using acceptance and commitment therapy, meta-cognitive therapy, dignity therapy and coaching have emerged, and whereas findings are promising, additional fully powered trials are required. Weaker evidence exists for counselling, support-based and narrative therapy interventions. Summary Efficacious, timely and acceptable psychological interventions are a necessary component of comprehensive cancer care. There is some way to go before the evidence conclusively points towards which interventions work for which cancer groups and for which specific outcomes. Methodological limitations must be addressed in future trials; at the forefront remains the need for fully powered, head-to-head comparison trials. Correspondence to Nicholas J. Hulbert-Williams, Chester Research Unit for the Psychology of Health, Department of Psychology, University of Chester, Parkgate Road, Chester CH1 4BJ, UK. Tel: +44 0 1244 511950; e-mail: n.hulbertwilliams@chester.ac.uk Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Pathophysiological mechanisms of exertional breathlessness in chronic obstructive pulmonary disease and interstitial lung disease

Purpose of review Breathlessness is a common and distressing symptom in patients with chronic obstructive pulmonary disease (COPD) and fibrotic interstitial lung disease (ILD), particularly during exercise. Effective medical management of exertional breathlessness in people living with COPD and fibrotic ILD is challenging for healthcare providers and requires an understanding of its mechanisms. Thus, in this brief review we summarize recent advances in our understanding of the pathophysiological mechanisms of exertional breathlessness in COPD and fibrotic ILD. Recent findings The collective results of recent physiological and clinical trials suggest that higher intensity ratings of exertional breathlessness in both COPD and fibrotic ILD compared to healthy control individuals is mechanistically linked to the awareness of greater neural respiratory drive (quantified using inspiratory muscle electromyography) needed to compensate for pathophysiological abnormalities in respiratory mechanics and pulmonary gas exchange efficiency. Summary Any therapeutic intervention capable of decreasing intrinsic mechanical loading of the respiratory system and/or increasing pulmonary gas exchange efficiency has the potential to decrease the prevalence and severity of activity-related breathlessness and improve related clinical and patient-reported outcomes (e.g., exercise tolerance and health-related quality of life) by decreasing neural respiratory drive in people with COPD and fibrotic ILD. Correspondence to Dennis Jensen, PhD, Department of Kinesiology and Physical Education, 475 Pine Avenue West, Montréal, Quebec, Canada, H2W 1S4. Tel: +1 514 398 4184; fax: +1 514 398 4186; e-mail: dennis.jensen@mcgill.ca Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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The role of primary care in supporting patients living with and beyond cancer

Purpose of review The prevalence of cancer survivors is increasing. Those living with and beyond a cancer diagnosis have a range of physical, psychosocial and practical needs. This review aims to discuss the role of primary care in meeting these needs. Recent findings Patients have increased contact with primary care after a cancer diagnosis but the role of the primary care team in the formal delivery of cancer aftercare is not clearly defined and varies depending on setting and context. Research suggests that both patients and health professionals are receptive to greater involvement of primary care, with informational and personal continuity of care, and good co-ordination of care being particularly valued by patients. Recent evidence indicates that shared care between oncologists and primary care physicians can be as effective as and more cost effective than secondary care-led follow-up, and that primary-care nurses could play a role in optimizing survivorship care. Summary The four pillars of primary care – contact, comprehensiveness, continuity and coordination – are recurring themes in the cancer survivorship literature and emphasize that the traditional core values of general practice lend themselves to innovative interventions to improve the efficiency and efficacy of survivorship care. Correspondence to Eila Watson, BSc, PhD, Professor, Supportive Cancer Care, School of Nursing and Midwifery, Faculty Health and Life Sciences, University of Oxford, Oxford OX3 0FL, UK. Tel: +1 865 482665; e-mail: ewatson@brookes.ac.uk Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Learning 30 years behind…

No abstract available

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Improving outcome in patients with prostate and kidney cancer: heading in the right direction?

No abstract available

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Evaluation of a Barcode Medication Administration Information System

When a medication administration error occurs, patient safety is endangered. Barcode medication administration system usage has been implemented to reduce medication errors. The purpose of this study was to evaluate barcode medication administration system usage outcomes. A survey based on DeLone and McLean's model of information systems success was utilized. The questionnaire, composed of 27 items, explored system quality, information quality, service quality, user satisfaction, and usage benefits. It was completed by 232 nurses. User satisfaction received the highest average score, and quality of information was the most critical factor related to this result (r = 0.83, P

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A novel complex neurological phenotype due to a homozygous mutation in FDX2

Abstract

Defects in iron–sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis.

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Correction: Metronomic Chemotherapy Enhances the Efficacy of Antivascular Therapy in Ovarian Cancer

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Pathology, Chemoprevention, and Preclinical Models for Target Validation in Barrett Esophagus

Despite esophageal adenocarcinoma (EAC) being the most widespread among gastrointestinal cancers, with an 11-fold increase in the risk of cancer for patients with Barrett esophagus (BE), its prognosis is still poor. There is a critical need to better perceive the biology of cancer progression and identification of specific targets that are the hallmark of BE's progression. This review explores the established animal models of BE, including genetic, surgical and nonsurgical approaches, potential chemoprevention targets, and the reasoning behind their applications to prevent Barrett-related EAC. The key methodological features in the design feasibility of relevant studies are also discussed. Cancer Res; 78(14); 3747–54. ©2018 AACR.

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Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. In vivo, Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy.Significance: These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy. Cancer Res; 78(14); 4022–35. ©2018 AACR.

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Metabolic Imaging of the Human Brain with Hyperpolarized 13C Pyruvate Demonstrates 13C Lactate Production in Brain Tumor Patients

Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. In vivo production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response.Significance: Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors.Graphical Abstract: https://ift.tt/2mjf7WM. Cancer Res; 78(14); 3755–60. ©2018 AACR.

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Evidence of Intertissue Differences in the DNA Damage Response and the Pro-oncogenic Role of NF-{kappa}B in Mice with Disengaged BRCA1-PALB2 Interaction

The BRCA1–PALB2–BRCA2 axis plays an essential role in DNA homologous recombination repair, defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage in vivo and how tumors develop from these cells remain poorly defined. Here, we analyzed several aspects of the DNA damage response in multiple tissues of Palb2-mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage. Following ionizing radiation, the mutant mice displayed higher levels of DNA breaks and stronger induction of p53 and p21, but continued DNA synthesis, reduced apoptosis, and accelerated tumor development. The differences in p21 induction, DNA synthesis, and apoptosis between wild-type and mutant mice were substantially more pronounced in the mammary gland than in the intestine, suggesting a potential contributing factor to the increased risk and the tissue specificity of BRCA/PALB2-associated tumor development. Moreover, the mutant mice showed higher levels of reactive oxygen species and constitutive activation of NF-κB, an antiapoptotic transcription factor inducible by both DNA damage and oxidative stress. Treatment of the mutant mice with an inhibitor of NF-κB reactivated apoptosis and delayed tumor development following radiation. Thus, our results also suggest a prosurvival and pro-oncogenic role of NF-κB in PALB2-mutant cells.Significance: This study explores novel tumor suppression mechanisms of the BRCA1-PALB2 DNA damage response pathway and implicates NF-κB activation as a protumorogenic event and possible therapeutic target. Cancer Res; 78(14); 3969–81. ©2018 AACR.

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Juxtacrine Signaling Inhibits Antitumor Immunity by Upregulating PD-L1 Expression

Programmed death-ligand 1 (PD-L1) is a well-known immune checkpoint protein that helps cancer cells evade immune response. Anti–PD-L1 immune therapy has been approved for the treatment of several advanced human cancers. Therefore, further understanding of the regulatory mechanisms of PD-L1 is critical to improve PD-L1–targeting immunotherapy. Recent studies indicated that contact-dependent pathways may regulate anticancer immunity, highlighting the importance of cell contact–induced signaling in cancer immunity. Here, we show that tumor cell contact upregulates PD-L1 expression and reduces T-cell–mediated cell killing through the membrane receptor tyrosine kinase ephrin receptor A10 (EphA10), which is not expressed in normal tissues except testis and is known to mediate cell contact–dependent juxtacrine signaling. Knockout of EphA10 in tumor cells increased T-cell–mediated antitumor immunity in syngeneic mouse models. EphA10 expression also correlated positively with PD-L1 in human breast tumor tissues. Together, our data reveal that in addition to paracrine/autocrine signaling, cell contact–mediated juxtacrine signaling also promotes PD-L1 expression, implying that tumor cells may escape immune surveillance via this mechanism and that targeting EphA10 to boost antitumor immunity may be a new immune checkpoint blockade strategy for female patients with breast cancer.Significance: Regulation of PD-L1 expression by cell contact–mediated signaling promotes immune escape in breast cancer and may lead to the development of an immunotherapy with less adverse effects in female patients. Cancer Res; 78(14); 3761–8. ©2018 AACR.

https://ift.tt/2zO2BZg

Detection of Urothelial Bladder Carcinoma via Microfluidic Immunoassay and Single-Cell DNA Copy-Number Alteration Analysis of Captured Urinary-Exfoliated Tumor Cells

The increasing incidence of bladder cancer and its high rate of recurrence over a 5-year period necessitate the need for diagnosis and surveillance amelioration. Cystoscopy and urinary cytology are the current tools, and molecular techniques such as BTA stat, NMP22, survivin mRNA, and urovysion FISH have attracted attention; however, they suffer from insufficient sensitivity or specificity. We developed a novel microfluidic approach for harvesting intact urinary-exfoliated tumor cells (UETC), either individually or in clusters, in a clean and segregated environment, which is crucial to minimize cross-contamination and misreads. To reliably and accurately identify UETC, our quantitative immunoassay involved concurrent use of two oncoproteins CK20 and CD44v6 antigen. CK20 is an intermediate filament protein overexpressed in urothelial tumors, and CD44v6 is a membrane adhesion molecule closely associated with cell invasion, tumor progression, and metastatic spread. Single-cell whole-genome sequencing on 12 captured UETCs and copy number alteration analysis showed that 11/12 (91.7%) of the immunofluorescence-identified UETCs possessed genomic instability. A total of 79 patients with bladder cancer and 43 age-matched normal controls (NC) were enrolled in the study. We detected considerably higher UETC counts in patients with bladder cancer versus the NC group [53.3 (10.7–1001.9) vs. 0.0 (0–3.0) UETCs/10 mL; P < 0.0001]. For bladder cancer detection, a stratified 10-fold cross-validation of training data reveals an overall predictive accuracy of 0.84 [95% confidence interval (CI), 0.76–0.93] with an 89.8% (95% CI, 71.5%–86.4%) for sensitivity and 71.5% (95% CI, 59.7%–83.3%) for specificity. Overall, the microfluidic immunoassay demonstrates increased sensitivity and specificity compared with other techniques for the detection of bladder cancer.Significance: A unique and promising diagnostic assay for bladder cancer is proposed with potential clinical utility as a complement for cytology. Cancer Res; 78(14); 4073–85. ©2018 AACR.

https://ift.tt/2zDATOF

Cancer-Associated Fibroblasts Drive Glycolysis in a Targetable Signaling Loop Implicated in Head and Neck Squamous Cell Carcinoma Progression

Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late-stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted HGF facilitates HNSCC progression; however, very little is known about the role of CAFs in HNSCC metabolism. Here, we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic FGF (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth in vitro and in vivo (P < 0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR.Significance: HNSCC cancer cells and CAFs have a metabolic relationship where CAFs secrete HGF to induce a glycolytic switch in HNSCC cells and HNSCC cells secrete bFGF to promote lactate consumption by CAFs. Cancer Res; 78(14); 3769–82. ©2018 AACR.

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Highlights from Recent Cancer Literature

https://ift.tt/2unul1G

Metabolic and Physiologic Imaging Biomarkers of the Tumor Microenvironment Predict Treatment Outcome with Radiation or a Hypoxia-Activated Prodrug in Mice

Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute to improved treatment strategies. Here, we define two imaging biomarkers that predict differences in tumor response to therapy: (i) partial oxygen pressure (pO2), measured by EPR imaging; and (ii) [1-13C] pyruvate metabolism rate, measured by hyperpolarized 13C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa2, and Su.86.86) were grown in mice. The median pO2 of the mature Hs766t, MiaPaCa2, and Su.86.86 tumors was 9.1 ± 1.7, 11.1 ± 2.2, and 17.6 ± 2.6 mm Hg, and the rate of pyruvate-to-lactate conversion was 2.72 ± 0.48, 2.28 ± 0.26, and 1.98 ± 0.51 per minute, respectively (n = 6, each). These results are in agreement with steady-state data of matabolites quantified by mass spectroscopy and histologic analysis, indicating glycolytic and hypoxia profile in Hs766t, MiaPaca2, and Su.86.86 tumors. Fractionated radiotherapy (5 Gy × 5) resulted in a tumor growth delay of 16.7 ± 1.6 and 18.0 ± 2.7 days in MiaPaca2 and Su.86.86 tumors, respectively, compared with 6.3 ± 2.7 days in hypoxic Hs766t tumors. Treatment with gemcitabine, a first-line chemotherapeutic agent, or the hypoxia-activated prodrug TH-302 was more effective against Hs766t tumors (20.0 ± 3.5 and 25.0 ± 7.7 days increase in survival time, respectively) than MiaPaCa2 (2.7 ± 0.4 and 6.7 ± 0.7 days) and Su.86.86 (4.7 ± 0.6 and 0.7 ± 0.6 days) tumors. Collectively, these results demonstrate the ability of molecular imaging biomarkers to predict the response of PDAC to treatment with radiotherapy and TH-302.Significance: pO2 imaging data and clinically available metabolic imaging data provide useful insight into predicting the treatment efficacy of chemotherapy, radiation, and a hypoxia-activated prodrug as monotherapies and combination therapies in PDAC tumor xenograft models. Cancer Res; 78(14); 3783–92. ©2018 AACR.

https://ift.tt/2zHwY39

Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis

Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling.Significance: CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia. Cancer Res; 78(14); 3995–4006. ©2018 AACR.

https://ift.tt/2zF6ijR

The miR-371~373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis

The vast majority of colorectal cancer–related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFβ signaling activity, and reduced expression of the miR-371∼373 cluster compared with nonmetastatic cultures. TGFβ receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371∼373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371∼373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371∼373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371∼373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371∼373 and ID1. Altogether, our results establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization.Significance: These findings establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel mechanism regulating self-renewal of tumor-initiating cell and metastatic colonization, potentially opening new concepts for therapeutic targeting of cancer metastasis.Graphical Abstract: https://ift.tt/2uyZBtL. Cancer Res; 78(14); 3793–808. ©2018 AACR.

https://ift.tt/2uqIjQb

Extracorporeal Photochemotherapy Drives Monocyte-to-Dendritic Cell Maturation to Induce Anticancer Immunity

Extracorporeal photochemotherapy (ECP) is a cancer immunotherapy for cutaneous T-cell lymphoma (CTCL) operative in more than 350 centers worldwide. Although its efficacy and favorable safety profile have driven its widespread use, elucidation of its underlying mechanism has been difficult. In this study, we identify the principal contributors to the anticancer immunotherapeutic effects of ECP, with the goal of enhancing potency and broadening applicability to additional malignancies. First, we scaled down the clinical ECP leukocyte-processing device to mouse size. Second, we used that miniaturized device to produce a cellular vaccine that regularly initiated therapeutic antimelanoma immunity. Third, we individually subtracted key factors from either the immunizing inoculum or the treated animal to ascertain their contribution to the in vivo antimelanoma response. Platelet-signaled monocyte-to-dendritic cell (DC) differentiation followed by sorting/processing/presentation of tumor antigens derived from internalized apoptotic tumor cells were absolute requirements. As in clinical ECP, immunogenic cell death of tumor cells was finely titrated by DNA cross-linkage mediated by photoactivated 8-methoxypsoralen (8-MOPA). ECP-induced tumor-loaded DC were effective immunotherapeutic agents only if they were spared exposure to 8-MOPA, indicating that healthy DC are required for ECP. Infusion of responder T cells into naïve tumor-challenged mice established the protective role of stimulated T-cell antitumor immunity. Collectively, these results reveal that selective antitumor effects of ECP are initiated by tumor antigen–loaded, ECP-induced DC, which promote potent collaboration between CD4 and CD8 tumor-specific T cells. These mechanistic insights suggest potential therapeutic applicability of ECP to solid tumors in addition to CTCL.Significance: These findings identify principal cellular contributors to the anticancer immunotherapeutic impact of ECP and suggest this treatment may be applicable to a broad spectrum of immunogenic malignancies. Cancer Res; 78(14); 4045–58. ©2018 AACR.

https://ift.tt/2zDAVWN

PTPN12/PTP-PEST Regulates Phosphorylation-Dependent Ubiquitination and Stability of Focal Adhesion Substrates in Invasive Glioblastoma Cells

Glioblastoma (GBM) is an invasive brain cancer with tumor cells that disperse from the primary mass, escaping surgical resection and invariably giving rise to lethal recurrent lesions. Here we report that PTP-PEST, a cytoplasmic protein tyrosine phosphatase, controls GBM cell invasion by physically bridging the focal adhesion protein Crk-associated substrate (Cas) to valosin-containing protein (Vcp), an ATP-dependent protein segregase that selectively extracts ubiquitinated proteins from multiprotein complexes and targets them for degradation via the ubiquitin proteasome system. Both Cas and Vcp are substrates for PTP-PEST, with the phosphorylation status of tyrosine 805 (Y805) in Vcp impacting affinity for Cas in focal adhesions and controlling ubiquitination levels and protein stability. Perturbing PTP-PEST–mediated phosphorylation of Cas and Vcp led to alterations in GBM cell-invasive growth in vitro and in preclinical mouse models. Collectively, these data reveal a novel regulatory mechanism involving PTP-PEST, Vcp, and Cas that dynamically balances phosphorylation-dependent ubiquitination of key focal proteins involved in GBM cell invasion.Significance: PTP-PEST balances GBM cell growth and invasion by interacting with the ATP-dependent ubiquitin segregase Vcp/p97 and regulating phosphorylation and stability of the focal adhesion protein p130Cas.Graphical Abstract: https://ift.tt/2mlMPuZ. Cancer Res; 78(14); 3809–22. ©2018 AACR.

https://ift.tt/2zJJdfO

Retraction: Histone Deacetylase Inhibitors Sensitize Prostate Cancer Cells to Agents that Produce DNA Double-Strand Breaks by Targeting Ku70 Acetylation

https://ift.tt/2uDFURt

An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer

Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo. In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/β-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer.Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis. Cancer Res; 78(14); 3823–33. ©2018 AACR.

https://ift.tt/2unK5S8

Correction: MUC1 Oncoprotein Promotes Refractoriness to Chemotherapy in Thyroid Cancer Cells

https://ift.tt/2zDAMTf

HP1{gamma} Promotes Lung Adenocarcinoma by Downregulating the Transcription-Repressive Regulators NCOR2 and ZBTB7A

Lung adenocarcinoma is a major form of lung cancer, which is the leading cause of cancer death. Histone methylation reader proteins mediate the effect of histone methylation, a hallmark of epigenetic and transcriptional regulation of gene expression. However, their roles in lung adenocarcinoma are poorly understood. Here, our bioinformatic screening and analysis in search of a lung adenocarcinoma–promoting histone methylation reader protein show that heterochromatin protein 1γ (HP1γ; also called CBX3) is among the most frequently overexpressed and amplified histone reader proteins in human lung adenocarcinoma, and that high HP1γ mRNA levels are associated with poor prognosis in patients with lung adenocarcinoma. In vivo depletion of HP1γ reduced K-RasG12D–driven lung adenocarcinoma and lengthened survival of mice bearing K-RasG12D–induced lung adenocarcinoma. HP1γ and its binding activity to methylated histone H3 lysine 9 were required for the proliferation, colony formation, and migration of lung adenocarcinoma cells. HP1γ directly repressed expression of the transcription-repressive regulators NCOR2 and ZBTB7A. Knockdown of NCOR2 or ZBTB7A significantly restored defects in proliferation, colony formation, and migration in HP1γ-depleted lung adenocarcinoma cells. Low NCOR2 or ZBTB7A mRNA levels were associated with poor prognosis in patients with lung adenocarcinoma and correlated with high HP1γ mRNA levels in lung adenocarcinoma samples. NCOR2 and ZBTB7A downregulated expression of tumor-promoting factors such as ELK1 and AXL, respectively. These findings highlight the importance of HP1γ and its reader activity in lung adenocarcinoma tumorigenesis and reveal a unique lung adenocarcinoma–promoting mechanism in which HP1γ downregulates NCOR2 and ZBTB7A to enhance expression of protumorigenic genes.Significance: Direct epigenetic repression of the transcription-repressive regulators NCOR2 and ZBTB7A by the histone reader protein HP1γ leads to activation of protumorigenic genes in lung adenocarcinoma. Cancer Res; 78(14); 3834–48. ©2018 AACR.

https://ift.tt/2zOvPa2

Molecular Subtype-Specific Immunocompetent Models of High-Grade Urothelial Carcinoma Reveal Differential Neoantigen Expression and Response to Immunotherapy

High-grade urothelial cancer contains intrinsic molecular subtypes that exhibit differences in underlying tumor biology and can be divided into luminal-like and basal-like subtypes. We describe here the first subtype-specific murine models of bladder cancer and show that Upk3a-CreERT2; Trp53L/L; PtenL/L; Rosa26LSL-Luc (UPPL, luminal-like) and BBN (basal-like) tumors are more faithful to human bladder cancer than the widely used MB49 cells. Following engraftment into immunocompetent C57BL/6 mice, BBN tumors were more responsive to PD-1 inhibition than UPPL tumors. Responding tumors within the BBN model showed differences in immune microenvironment composition, including increased ratios of CD8+:CD4+ and memory:regulatory T cells. Finally, we predicted and confirmed immunogenicity of tumor neoantigens in each model. These UPPL and BBN models will be a valuable resource for future studies examining bladder cancer biology and immunotherapy.Significance: This work establishes human-relevant mouse models of bladder cancer. Cancer Res; 78(14); 3954–68. ©2018 AACR.

https://ift.tt/2uqIj2D

SNHG6 Acts as a Genome-Wide Hypomethylation Trigger via Coupling of miR-1297-Mediated S-Adenosylmethionine-Dependent Positive Feedback Loops

Aberrant genome-wide hypomethylation and long noncoding RNA (lncRNA) dysregulation are associated with hepatocarcinogenesis. However, whether a relationship between the two exists remains largely unknown. S-adenosylmethionine (SAMe)-dependent methylation is a critical factor in genomic methylation. We previously found that SNHG6 lncRNA acted as an oncogene in hepatocarcinogenesis and could be considered a potential prognostic indicator for hepatocellular carcinoma (HCC). Here we verify that SNHG6 leads to genome-wide hypomethylation in hepatoma cells and that SNHG6 negatively correlates with the steady-state SAMe concentration in vivo and in vitro. SNHG6 suppressed MAT1A protein expression by activating the miR-1297/FUS pathway to regulate nucleocytoplasmic shuttling of MAT1A mRNA. In addition, SNHG6 promoted expression of MAT2A by suppressing direct binding of miR-1297 to the MAT2A 3′UTR. SNHG6 regulated steady-state SAMe levels via coupling of two miR-1297–mediated SAMe-dependent positive feedback loops. Interestingly, the effect of SNHG6 on genome-wide methylation was inhibited by exogenous SAMe within a certain concentration range. These results suggest that single lncRNA dysregulation can lead to aberrant genome-wide hypomethylation by inhibiting SAMe production in HCC and that exogenous SAMe may be beneficial in the treatment of HCC.Significance: These findings explore the role of SNHG6 lncRNA in suppressing production of the universal methyl donor SAMe and its impact on global DNA methylation levels in liver cancer and highlight the potential benefit of SAMe for the treatment of liver cancer. Cancer Res; 78(14); 3849–64. ©2018 AACR.

https://ift.tt/2uqaMWq

Regulation of neutrophils in type 2 immune responses

Lukas E M Heeb | Cecilie Egholm | Daniela Impellizzieri | Frederike Ridder | Onur Boyman

https://ift.tt/2Ng2hUY

Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation

Abstract

Background

Exosomes are extracellular vesicles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum. Their key function being intercellular communication with both neighbouring as well as distant cells. Cancer exosomes have been shown to regulate organ-specific metastasis. However, little is known about the functional differences and molecular consequences of normal cells responding to exosomes derived from normal cells compared to those derived from cancer cells.

Methods

Here, we characterised and compared the transcriptome profiles of primary human normal oral keratinocytes (HNOK) in response to exosomes isolated from either primary HNOK or head and neck squamous cell carcinoma (HNSCC) cell lines.

Results

In recipient HNOK cells, we found that regardless of normal or cancer derived, exosomes altered molecular programmes involved in matrix modulation (MMP9), cytoskeletal remodelling (TUBB6, FEZ1, CCT6A), viral/dsRNA-induced interferon (OAS1, IFI6), anti-inflammatory (TSC22D3), deubiquitin (OTUD1), lipid metabolism and membrane trafficking (BBOX1, LRP11, RAB6A). Interestingly, cancer exosomes, but not normal exosomes, modulated expression of matrix remodelling (EFEMP1, DDK3, SPARC), cell cycle (EEF2K), membrane remodelling (LAMP2, SRPX), differentiation (SPRR2E), apoptosis (CTSC), transcription/translation (KLF6, PUS7). We have also identified CEP55 as a potential cancer exosomal marker.

Conclusions

In conclusion, both normal and cancer exosomes modulated unique gene expression pathways in normal recipient cells. Cancer cells may exploit exosomes to confer transcriptome reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis. Molecular pathways and biomarkers identified in this study may be clinically exploitable for developing novel liquid-biopsy based diagnostics and immunotherapies.

https://ift.tt/2L8Psyl

Sport and dance interventions for healthy young people (15-24 years) to promote subjective well-being: a systematic review

Objective

To review and assess effectiveness of sport and dance participation on subjective well-being outcomes among healthy young people aged 15–24 years.

Design

Systematic review.

Methods

We searched for studies published in any language between January 2006 and September 2016 on PsychINFO, Ovid MEDLINE, Eric, Web of Science (Arts and Humanities Citation Index, Social Science and Science Citation Index), Scopus, PILOTS, CINAHL, SPORTDiscus and International Index to Performing Arts. Additionally, we searched for unpublished (grey) literature via an online call for evidence, expert contribution, searches of key organisation websites and the British Library EThOS database, and a keyword Google search. Published studies of sport or dance interventions for healthy young people aged 15–24 years where subjective well-being was measured were included. Studies were excluded if participants were paid professionals or elite athletes, or if the intervention was clinical sport/dance therapy. Two researchers extracted data and assessed strength and quality of evidence using criteria in the What Works Centre for Wellbeing methods guide and GRADE, and using standardised reporting forms. Due to clinical heterogeneity between studies, meta-analysis was not appropriate. Grey literature in the form of final evaluation reports on empirical data relating to sport or dance interventions were included.

Results

Eleven out of 6587 articles were included (7 randomised controlled trials and 1 cohort study, and 3 unpublished grey evaluation reports). Published literature suggests meditative physical activity (yoga and Baduanjin Qigong) and group-based or peer-supported sport and dance has some potential to improve subjective well-being. Grey literature suggests sport and dance improve subjective well-being but identify negative feelings of competency and capability. The amount and quality of published evidence on sport and dance interventions to enhance subjective well-being is low.

Conclusions

Meditative activities, group and peer-supported sport and dance may promote subjective well-being enhancement in youth. Evidence is limited. Better designed studies are needed.

Trial registration number

CRD42016048745; Results.

https://ift.tt/2mlXnua

FDA Announces Voluntary Recall of Several Medicines Containing Valsartan Following Detection of an Impurity

July 13, 2018 -- The U.S. Food and Drug Administration is alerting health care professionals and patients of a voluntary recall of several drug products containing the active ingredient valsartan, used to treat high blood pressure and heart failure....

https://ift.tt/2uzDF1t

Jury Awards $4.62B in Johnson & Johnson Talcum Powder Lawsuit

FRIDAY, July 13, 2018 -- A jury says Johnson & Johnson must pay $4.62 billion to 22 women who allege they developed ovarian cancer after using the company's Baby Powder and Shower to Shower brand talcum powder as part of their daily feminine...

https://ift.tt/2Lfdjw6

Subcellular Fractionation from Fresh and Frozen Gastrointestinal Specimens

Here, we present a protocol to perform a simple cellular fractionation for the subcellular separation of cytoplasmic and nuclear proteins in human fresh and frozen intestinal biopsies.

https://ift.tt/2Jr0VEp

Ultralow Input Genome Sequencing Library Preparation from a Single Tardigrade Specimen

Contamination during the genomic sequencing of microscopic organisms remains a large problem. Here, we show a method to sequence the genome of a tardigrade from a single specimen with as little as 50 pg of genomic DNA without whole genome amplification to minimize the risk of contamination.

https://ift.tt/2JqROU3

SYSTEMATIC SCREENING FOR PRIMARY SCLEROSING CHOLANGITIS WITH MAGNETIC RESONANCE CHOLANGIOGRAPHY IN INFLAMMATORY BOWEL DISEASE

Primary sclerosing cholangitis (PSC) is a major concern in inflammatory bowel disease (IBD).

https://ift.tt/2L8guWB

Stomata Tape-Peel: An Improved Method for Guard Cell Sample Preparation

This protocol describes a method of preparing enriched stomatal guard cells that is useful for physiological and other biological studies.

https://ift.tt/2Ljr4Xq

Obesity is Independently Associated with Higher Annual Burden and Costs of Hospitalization in Patients with Inflammatory Bowel Diseases

Approximately 15%–40% patients with inflammatory bowel diseases (IBD) are obese. There is an inconsistent association between obesity and IBD phenotype and course. We conducted a nationally representative cohort study to estimate and compare the burden, costs, and causes for hospitalization in obese vs. non-obese patients with IBD.

https://ift.tt/2JpquFG

Treatments for Crohn’s Disease-associated Bowel Damage: a Systematic Review

Despite significant advances in the treatment of Crohn's disease (CD), most patients still develop stricturing or penetrating complications that require surgical resections. We performed a systematic review of mechanisms and potential treatments for tissue damage lesions in CD patients.

https://ift.tt/2Lf01zI

Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients with Ulcerative Colitis

Tofacitinib is an oral, small molecule inhibitor of JAK for the treatment of ulcerative colitis (UC). We evaluated the onset of symptom improvement in post-hoc analyses of data from 2 phase 3 trials of induction therapy with tofacitinib in patients with UC (OCTAVE Induction 1 and 2).

https://ift.tt/2LgqIAP

Risk of Bias Analysis of Systematic Reviews of Probiotics for Treatment of Irritable Bowel Syndrome

https://ift.tt/2LhxPMy

Lower Annual rate of Progression of Short-segment vs Long-segment Barrett’s Esophagus to Esophageal Adenocarcinoma

European guidelines recommend different surveillance intervals of non-dysplastic Barrett's esophagus (NDBE) based on segment length, as opposed to guidelines in the United States, which do recommend surveillance intervals based on BE length. We studied rates of progression of NDBE to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in patients with short-segment BE using the definition of BE in the latest guidelines (length ≥1 cm).

https://ift.tt/2Lo5jpG

Obesity and Weight Gain Are Associated With Progression of Fibrosis in Patients with Non-alcoholic Fatty Liver Disease

The effects of weight change on the progression of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) in the general population are unclear. We evaluated the association of weight change and baseline body mass index (BMI) with fibrosis progression, determined by non-invasive measurement of a marker, in young and middle-aged adults with NAFLD.

https://ift.tt/2LdCCi9

Is Biology or the Endoscopist to Blame for Post-colonoscopy Colorectal Cancer?

https://ift.tt/2JpuZ3c

Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir With Concurrent Use of Acid-Reducing Agents in Patients With Chronic HCV Infection

Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents.

https://ift.tt/2LbUjyO

P25. Time specific neuronal activation and its association with cognitive control over emotions

Successful cognitive control over emotions (CCE) can impede a biased attention towards negative valenced information ('Negativity Bias', NB) which can be observed in various psychiatric disorders. On a neurophysiological level CCE and the NB can be investigated with event related potentials (ERPs). The goal of the current study is to investigate the NB and CCE with ERPs on feedback as its emotional valence is largely based on the interpretation by the participant.

https://ift.tt/2LbB5Ju

Drugs used for euthanasia: a repeated population-based mortality follow-back study in Flanders, Belgium, 1998 – 2013

– According to guideline recommendations, barbiturates and neuromuscular relaxants are the recommended drugs for euthanasia.

https://ift.tt/2KUSEOF

Grieving to Grieve

As the physician leader for Schwartz Center Rounds at City of Hope, I recently facilitated a panel of clinicians that spoke to the topic "A loss that lingers". As all the panelists reflected on their stories and shared them with the audience, it quickly became apparent that some of them had not addressed their own feelings around their stories for a long time, the rounds that day for some individuals being the very first time that they were having to face these emotions. It was evident that their personal grief over these patient losses had been buried somewhere deep inside them for years, summoned by fate on this date to give it due justice and necessary closure.

https://ift.tt/2NiBRSm

VALIDATION OF TWO PAIN ASSESSMENT TOOLS UTILIZING A STANDARDIZED NOCICEPTIVE STIMULATION IN CRITICALLY ILL ADULTS

The Behavioral Pain Scale (BPS) or the Critical-Care Pain Observation Tool (CPOT) are recommended in practice guidelines for pain assessment in critically ill adults unable to self-report. However, their use in another language requires cultural adaptation and validation testing.

https://ift.tt/2KZRbXt

Fan Therapy is Effective in Relieving Dyspnea in Terminally Ill Cancer Patients: A Parallel Arm, Randomized Controlled Trial

Dyspnea is a common distressing symptom among patients with advanced cancer.

https://ift.tt/2NcTdzS

Psychometric properties of the Needs Assessment Tool - Progressive Disease Cancer in UK Primary Care

The assessment of patients' needs for care is a critical step in achieving patient-centred cancer care. Tools can be used to assess needs and inform care planning. The Needs Assessment Tool: Progressive Disease- Cancer (NAT: PD-C) is an Australian oncology clinic tool for assessment by clinicians of patients' and carers' palliative care needs. This has not been validated in the UK Primary Care setting.

https://ift.tt/2KUSuXz

Frequency-encoded multicolor fluorescence imaging with single-photon counting color-blind detection

Standard fluorescence microscopy relies on filter-based detection of emitted photons after fluorophore excitation at the appropriate wavelength. While of enormous utility to the biological community, the implementation of approaches for simultaneous multicolor fluorescence imaging is commonly challenged by the large spectral overlap between different fluorophores. In here we describe an alternative multicolor fluorescence imaging methodology that exclusively relies on the absorption spectra of the fluorophores instead of their fluorescence emissions.

https://ift.tt/2L10LsY

Fluorinated Alcohols’ Effects on Lipid Bilayer Properties

Fluorinated alcohols (fluoroalcohols) have physico-chemical properties that make them excellent solvents of peptides, proteins and other compounds. Like other alcohols, fluoroalcohols also alter membrane protein function and lipid bilayer properties and stability. Thus the questions arise: how potent are fluoroalcohols as lipid bilayer-perturbing compounds; could small residual amounts that remain after adding compounds dissolved in fluoroalcohols alter lipid bilayer properties sufficiently to affect membranes and membrane protein function; and do they behave like other alcohols? To address these questions, we used a gramicidin-based fluorescence assay to determine the bilayer-modifying potency of selected fluoroalcohols: trifluoroethanol (TFE); hexafluoroisopropanol (HFIP); and perfluoro-tert-butanol (PFTB).

https://ift.tt/2L119aU

Local DNA sequence controls asymmetry of DNA unwrapping from nucleosome core particles

DNA is tightly wrapped around histone proteins in nucleosome core particles (NCPs), yet must become accessible for processing in the cell. This accessibility, a key component of transcription regulation, is influenced by the properties of both the histone proteins and the DNA itself. Small angle x-ray scattering with contrast variation (CV-SAXS) is used to examine how sequence variations affect DNA unwrapping from NCPs, at different salt concentrations. Salt destabilizes NCPs, populating multiple unwrapped states as many possible unwrapping pathways are explored by the complexes.

https://ift.tt/2NhGXOV

Cytoskeletal mechanisms of axonal contractility

Mechanotransduction is likely to be an important mechanism of signalling in thin, elongated cells like neurons. Maintenance of pre-stress or rest tension may facilitate mechanotransduction in these cells. In recent years, functional roles for mechanical tension in neuronal development and physiology are beginning to emerge but the cellular mechanisms regulating neurite tension remain poorly understood. Active contraction of neurites is a potential mechanism of tension regulation. In this study, we have explored cytoskeletal mechanisms mediating active contractility of neuronal axons.

https://ift.tt/2Nj4xuB

Stepwise C-Terminal Truncation of Cardiac Troponin T Alters Function at Low and Saturating Ca2+

Activation of striated muscle contraction occurs in response to Ca2+ binding to troponin C (TnC). The resulting reorganization of troponin repositions tropomyosin on actin and permits activation of myosin catalyzed ATP hydrolysis. It now appears that the C-terminal 14 amino acids of cardiac troponin T (TnT) control the level of activity at both low and high Ca2+. We made a series of C-terminal truncation mutants of human cardiac troponin T, isoform 2, to determine if the same residues of TnT are involved in the low and high Ca2+ effects.

https://ift.tt/2L10KVW

Trends in Albuminuria and GFR Among Adolescents in the United States, 1988-2014

Albuminuria and low estimated glomerular filtration rate (eGFR) define chronic kidney disease in adults and youth. Different from adults, the burden of abnormal kidney markers among youth in the general United States population is largely unknown.

https://ift.tt/2zHk0mf

Reply

We would like to respond to Dr Koumbourlis' letter. We took the approach in this analysis to focus on substantive, clinically meaningful change in respiratory status as our outcome measure. Physiologic changes of lung compliance could be measured in infants born premature exposed to diuretics in modern neonatal intensive care units; however, we feel that weaning off of positive pressure ventilation is important to families and staff more than short-term potential changes in peak inspiratory pressure and fraction of inspired oxygen.

https://ift.tt/2zCc3P4

Hamman's Sign in a Patient with Spontaneous Pneumomediastinum

A previously healthy, 14-year-old boy presented with chest pain lasting 1 day. He had no complaints of fever, cough, dyspnea, nausea, or vomiting nor did he have any history of asthma or trauma. His height, weight, and body mass index was 165 cm, 44 kg, and 16, respectively. His vital signs were body temperature 37.0°C, heart rate 85/minutes, respiratory rate 24/minutes, and oxygen saturation 98% in room air. Upon physical examination, a crackling sound synchronous with heartbeat, the so-called Hamman's sign, was noted on cardiac auscultation in the lower left sternal border (Audio; available at www.jpeds.com).

https://ift.tt/2uojmFb

On the Gendering of Plasma: What is Transfusion-Related Acute Lung Injury to Bronchopulmonary Dysplasia?

"When I use a word," Humpty Dumpty said to Alice, in rather a scornful tone, "it means just what I choose it to mean—neither more nor less."

https://ift.tt/2zISiFK

Antimicrobial Potential of Caffeic Acid against Staphylococcus aureus Clinical Strains

Phenolic compounds constitute one of the most promising and ubiquitous groups with many biological activities. Synergistic interactions between natural phenolic compounds and antibiotics could offer a desired alternative approach to the therapies against multidrug-resistant bacteria. The objective of the presented study was to assess the antibacterial potential of caffeic acid (CA) alone and in antibiotic-phytochemical combination against Staphylococcus aureus reference and clinical strains isolated from infected wounds. The caffeic acid tested in the presented study showed diverse effects on S. aureus strains with the minimum inhibitory concentration (MIC) varied from 256 μg/mL to 1024 μg/mL. The supplementation of Mueller-Hinton agar (MHA) with 1/4 MIC of CA resulted in augmented antibacterial effect of erythromycin, clindamycin, and cefoxitin and to the lesser extent of vancomycin. The observed antimicrobial action of CA seemed to be rather strain than antibiotic dependent. Our data support the notion that CA alone exerts antibacterial activity against S. aureus clinical strains and has capacity to potentiate antimicrobial effect in combination with antibiotics. The synergy between CA and antibiotics demonstrates its potential as a novel antibacterial tool which could improve the treatment of intractable infections caused by multidrug-resistant strains.

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Natural Products as a Source for New Leads in Cancer Research and Treatment

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Probabilistic Risk Assessment of Inorganic Arsenic via Consumption of Herbs Collected in Thailand

Total and inorganic arsenic contents in ten commonly consumed Thai herbs, namely, bird's eye chili, cayenne pepper, celery, garlic, holy basil, kitchen mint, lemongrass, pepper, shallot, and sweet basil, were determined using atomic absorption spectrometry coupled with a hydride generation system (HG-AAS). Total arsenic contents in fresh herbs and lyophilized herbs ranged from 3.39 to 119 ng/g wet weight (wet wt) and from 41.0 to 156 ng/g dry weight (dry wt), respectively. Inorganic arsenic contents in fresh herbs and lyophilized herbs ranged from 2.09 to 26.9 ng/g (wet wt) and from 23.5 to 55.5 ng/g (dry wt), respectively. Percentages of inorganic arsenic to total arsenic in herbs ranged from 22.7 to 62.0%. High percentages of inorganic arsenic to total arsenic were found in celery, lemongrass and sweet basil. Total arsenic contents in the studied herbs were lower than the maximum limits of Thai and Chinese regulatory standards, set at 2,000 ng/g in foods (excluding aquatic animals and seafood) and 500 ng/g in fresh vegetables, respectively. Total and inorganic arsenic contents in the studied herbs were comparable to or lower than the levels found in other studies in the EU and China. Lifetime average daily dose (LADD) and cancer risk (CR) of inorganic arsenic exposure to commonly consumed herbs were evaluated using probabilistic risk assessment (PRA) by @RISK software version 6.0 of Palisade cooperation. All calculated LADD and CR values from all herbs did not exceed the acceptable levels. It can be concluded that there were very low cancer risks of inorganic arsenic exposure from the consumption of the studied herbs.

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Antiulcer Effect of Honey in Nonsteroidal Anti-Inflammatory Drugs Induced Gastric Ulcer Model in Rats: A Systematic Review

Background. Peptic ulcer is a basic term for ulcers on the lower oesophagus, stomach, or jejunum. The specific term for ulcer in the stomach is gastric ulcer. The extensive use of honey around the globe helps researchers to study the usefulness of honey. Many studies had already been conducted and proved the effectiveness of honey in treating gastric ulcer. Methods. A systematic review of the literature was conducted to identify relevant studies on honey used as an alternative treatment of gastric ulcer cause by NSAIDs. A comprehensive search was conducted in Medline, SCOPUS, and Ebscohost. The main criteria used were articles published in English and using NSAIDs-induced gastric ulcer in rat's model and those reporting the effectiveness of honey. Results. Articles published between 2001 and 2014 were identified to be relevant in studies related to the inclusion criteria. The literature search found 30 potential and closely related articles in this review, but only 5 articles were taken which meet the criteria needed to be fulfilled. Conclusions. All studies in this review reported the efficacy of honey for gastric ulcer based on its antioxidant and cytoprotective activities. Most of the studies conducted used different types of honey at various doses on rats. Future studies should be conducted to identify the appropriate dose for humans to achieve similar gastroprotective effects.

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Genotypic and Phenotypic Relationship among Yield Components in Rice under Tropical Conditions

The associations among yield-related traits and the pattern of influence on rice grain yield were investigated. This evaluation is important to determine the direct and indirect effects of various traits on yield to determine selection criteria for higher grain yield. Fifteen rice genotypes were evaluated under tropical condition at five locations in two planting seasons. The experiment was laid out in a randomized complete block design with three replications across the locations. Data were collected on vegetative and yield components traits. The pooled data based on the analysis of variance revealed that there were significant differences () among the fifteen genotypes for all the characters studied except for panicle length and 100-grain weight. Highly significant and positive correlations at phenotypic level were observed in grain weight per hill (0.796), filled grains per panicle (0.702), panicles per hill (0.632), and tillers per hill (0.712) with yield per hectare, while moderate positive correlations were observed in flag leaf length to width ratio (0.348), days to flowering (0.412), and days to maturity (0.544). By contrast, unfilled grains per panicle (-0.225) and plant height (-0.342) had a negative significant association with yield per hectare. Filled grains per panicle (0.491) exhibited the maximum positive direct effect on yield followed by grain weight per hill (0.449), while unfilled grain per panicle (-0.144) had a negative direct effect. The maximum indirect effect on yield per hectare was recorded by the tillers per hill through the panicles per hill. Therefore, tillers per hill, filled grains per panicle, and grain weight per hill could be used as selection criteria for improving grain yield in rice.

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Advances in Emerging and Neglected Infectious Diseases 2018

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Frontal EEG Temporal and Spectral Dynamics Similarity Analysis between Propofol and Desflurane Induced Anesthesia Using Hilbert-Huang Transform

Electroencephalogram (EEG) signal analysis is commonly employed to extract information on the brain dynamics. It mainly targets brain status and communication, thus providing potential to trace differences in the brain's activity under different anesthetics. In this article, two kinds of gamma-amino butyric acid (type A -GABAA) dependent anesthetic agents, propofol and desflurane (28 and 23 patients), were studied and compared with respect to EEG spectrogram dynamics. Hilbert-Huang Transform (HHT) was employed to compute the time varying spectrum for different anesthetic levels in comparison with Fourier based method. Results show that the HHT method generates consistent band power (slow and alpha) dominance pattern as Fourier method does, but exhibits higher concentrated power distribution within each frequency band than the Fourier method during both drugs induced unconsciousness. HHT also finds slow and theta bands peak frequency with better convergence by standard deviation (propofol-slow: 0.46 to 0.24; theta: 1.42 to 0.79; desflurane-slow: 0.30 to 0.25; theta: 1.42 to 0.98) and a shift to relatively lower values for alpha band (propofol: 9.94 Hz to 10.33 Hz, desflurane 8.44 Hz to 8.84 Hz) than Fourier one. For different stage comparisons, although HHT shows significant alpha power increases during unconsciousness stage as the Fourier did previously, it finds no significant high frequency (low gamma) band power difference in propofol whereas it does in desflurane. In addition, when comparing the HHT results within two groups during unconsciousness, high beta band power in propofol is significantly larger than that of desflurane while delta band power behaves oppositely. In conclusion, this study convincingly shows that EEG analyzed here considerably differs between the HHT and Fourier method.

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Comparison of LI-RADS v.2017 and ESGAR Guidelines Imaging Criteria in HCC Diagnosis Using MRI with Hepatobiliary Contrast Agents

Purpose. The purpose of this study was to assess and compare diagnostic ability of LI-RADS (LR) v. 2017 and ESGAR guidelines in hepatocellular carcinoma (HCC) diagnosis using MRI with hepatobiliary contrast agents. Methods. Seventy pathologically confirmed lesions in 32 patients (24 males and 8 females) who had MRI with hepatobiliary contrast done before surgery or biopsy were reviewed retrospectively. Six lesions were

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A Rare Case of Vascular Leiomyosarcoma Originating from a Branch Vessel of the External Iliac Vein

Leiomyosarcoma arising from the external iliac vein is uncommon. This is a report of a 51-year-old Japanese man with venous leiomyosarcoma originating from a branch vessel of the left external iliac vein. The tumor was found during a medical examination, and the patient had no symptoms. Computed tomography showed a 72 × 49 mm mass adjacent to the left external iliac vein. The tumor was resected en-block along with ligation of the external iliac vein due to strong adhesion with the tumor. Histological examination showed venous leiomyosarcoma, and its origin was thought to be a branch vessel of the left external iliac vein. The patient has remained free from recurrence at 30 months after surgery.

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Tualang Honey Reduced Neuroinflammation and Caspase-3 Activity in Rat Brain after Kainic Acid-Induced Status Epilepticus

The protective effect of tualang honey (TH) on neuroinflammation and caspase-3 activity in rat cerebral cortex, cerebellum, and brainstem after kainic acid- (KA-) induced status epilepticus was investigated. Male Sprague-Dawley rats were pretreated orally with TH (1.0 g/kg body weight) five times at 12 h intervals. KA (15 mg/kg body weight) was injected subcutaneously 30 min after last oral treatment. Rats were sacrificed at 2 h, 24 h, and 48 h after KA administration. Neuroinflammation markers and caspase-3 activity were analyzed in different brain regions 2 h, 24 h, and 48 h after KA administration. Administration of KA induced epileptic seizures. KA caused significant (p

https://ift.tt/2Lk2NRc

Effects of Low-Intensity Pulsed Ultrasound on Knee Osteoarthritis: A Meta-Analysis of Randomized Clinical Trials

Background. Osteoarthritis (OA) is a common degeneration disease characterized with joint pain. The aim of the present study was to systemically review the effects of LIPUS on pain relief and functional recovery in patients with knee osteoarthritis (OA). Methods. PubMed, Embase, and Cochrane Library were searched manually for researches on LIPUS treatment in patients with knee OA from 1945 to July 2017. Two investigators independently selected the studies according to the inclusion and exclusion criteria, extracted the concerned data, and assessed the included studies. Meta-analysis was performed to evaluate VAS, WOMAC, and ambulation speed between control and LIPUS groups. Results. Five studies were selected in this study. Compared with control group, LIPUS group received a decrease of pain intensity with moderate heterogeneity (-0.79, 95% CI, -1.57 to 0.00; I2 = 65%, P = 0.04) by VAS and improvement in knee function by WOMAC (-5.30, 95% CI, -2.88 to -7.71; I2 = 44%, P = 0.17). No significant improvement was found in ambulation speed (0.08 m/s, 95% CI, -0.02 to 0.18 m/s; I2 = 68%, P = 0.03). Conclusion. The present study includes 5 high quality randomized controlled trials. The result indicated that LIPUS, used to treat knee OA without any adverse effect, had a beneficial effect on pain relief and knee functional recovery. More evidence is needed to prove whether LIPUS is effective in improving walking ability.

https://ift.tt/2uqlyMa

Physical Activity and Health-Related Fitness of Adolescents within the Juvenile Justice System

Background. The purpose of this study was to examine the physical activity patterns and health-related fitness levels of adolescents within the Juvenile Justice System. Methods. Participants included 68 adolescents (Mean age = 17.1 ± 1.0 years) in two secure Juvenile Justice correctional facilities in the Western USA. Moderate-to-vigorous physical activity (MVPA) was monitored for one week using the ActiGraph GT9X accelerometer. Health-related fitness was measured using the FITNESSGRAM test battery. Results. Adolescents averaged 43.3±21.6 minutes of MVPA per weekday compared to 42.7±27.5 per weekend day. During school hours, adolescents accumulated 17.1±9.0 minutes of MVPA compared to 5.9±3.4 minutes before school and 21.0±13.6 minutes after school. Adolescents averaged 18.9±11.0 push-ups, 44.5±26.4 curl-ups, 34.7±24.8 PACER laps, and 22.1%±10.0% body fat. Conclusions. Adolescents within the Juvenile Justice System are falling short of the recommended 60 minutes of MVPA per day and 30 minutes of MVPA during school and also need to improve their health-related fitness, especially cardiorespiratory endurance.

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Incidence of Intestinal Infectious Diseases due to Protozoa and Bacteria in Mexico: Analysis of National Surveillance Records from 2003 to 2012

Background. According to national epidemiological surveillance records, in Mexico six intestinal infectious diseases (IID) are among the top infectious communicable diseases. However, their incidence, relative importance, and spatial patterns have not been studied in detail. Aims. We examine the epidemiology of IID due to bacteria and protozoa to identify which diseases are most important at two spatial scales, what is their integrated importance locally, and how their incidence correlates with Human Development Index (HDI). Methods. We retrieved yearly number of new cases of eight IID from the national epidemiological morbidity report from 2003 to 2012 at the national level, by state, and to assess such information at a higher spatial resolution we included the municipalities for Mexico City. However, no comparisons were made to other municipalities due to unavailability of data. We compared incidence, obtained the disease-specific relative importance, and inspected spatial patterns for the integrated incidence. Finally, we tested whether HDI is correlated with incidence. Results. We found that, except for two diseases, the relative importance of the other six IID contrasted not only between the national level and Mexico City, but also among states and municipalities in Mexico City. Besides, at both scales the distribution of the incidence showed disease-specific spatial patterns. Finally, there was a lack of consistent correlation between HDI and individual IID at both scales. Conclusion. Our results emphasize the need for local disease-focused selective models for control and prevention of IID. The maps displaying our analyses of epidemiological similarities may be used in orienting such effort.

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The Thomsen-Friedenreich Antigen-Specific Antibody Signatures in Patients with Breast Cancer

Alterations in the glycosylation of serum total immunoglobulins show these antibodies to have a diagnostic potential for cancer but the disease-related Abs to the tumor-associated antigens, including glycans, have still poorly been investigated in this respect. We analysed serum samples from patients with breast carcinoma (n = 196) and controls (n = 64) for the level of Thomsen-Friedenreich (TF) antigen-specific antibody isotypes, their sialylation, interrelationships, and the avidity by using ELISA with the synthetic TF-polyacrylamide conjugate as an antigen and the sialic acid-specific Sambucus nigra agglutinin (SNA) and ammonium thiocyanate as a chaotrope. An increased sialylation of IgG and IgM, but a lower SNA reactivity of IgA TF antibodies, and a higher level and avidity of the TF-specific IgA were found in cancer patients. Other cancer-related signatures were the highly significant increase of the IgG/IgA ratio and the very low SNA/IgA index in cancer, including patients with an early stage of the disease. These changes showed a good diagnostic potential with about 80% accuracy. Thus, the level of naturally occurring anti-TF antigen antibodies, their sialylation profile, isotype distribution, and avidity displayed cancer-specific changes that could serve as novel noninvasive Ab-based biomarkers for early breast cancer.

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Isolation of a Trypanosome Related to Trypanosoma theileri (Kinetoplastea: Trypanosomatidae) from Phlebotomus perfiliewi (Diptera: Psychodidae)

The Trypanosoma theileri group includes several trypanosome species hardly distinguishable due to the lack of discriminating morphological characters. Trypanosomes belonging to this group have been isolated from different bovine, ovine, and cervids in Europe, Africa, Asia, and Americas. The principal vectors of the T. theileri group are considered tabanid flies; however, T. melophagium is transmitted exclusively by sheep keds. In 2016, 128 sand flies out of 2,728 trapped in Valsamoggia municipality, Italy, were individually dissected and an unknown trypanosome strain, named TrPhp1, was isolated from a female of the sand fly Phlebotomus perfiliewi. Sequence analysis placed this trypanosome in the T. theileri group with very high homology to other trypanosomes detected in European cervids. This is the first report of the T. theileri group isolation from a sand fly, and the possible role of this insect group in the trypanosome transmission cycle is discussed. Within the T. theileri group, the phylogenetic analysis distinguished several lineages, which, unfortunately, do not correspond with their host specificity and their taxonomic status remains ambiguous.

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Disseminated BCG-osis with haemophagocytosis, tubercular bacteraemia, and unusual haematological findings with its haematology analyser-based expression

Abstract

Infantile disseminated BCG-osis is an uncommon complication of BCG vaccination and the presence of haemophagocytic lymphohistiocytosis (HLH) further complicates the clinical course due to its fatal outcome. Here, we describe a rare case of disseminated BCG-osis with HLH in a 3-month-old male child and the unusual morphological findings in the peripheral blood with its haematology analyser-based expression. The child presented with fever, failure to thrive, hepatosplenomegaly, erythematous skin rashes, and left axillary lymphadenopathy with history of BCG vaccination at birth. He was the first born of second-degree consanguineous marriage with no significant family history of immunodeficiency disorders. Laboratory findings included anaemia, thrombocytopenia, hyperferritinaemia, hypertriglyceridaemia, and hypofibrinogenaemia which supported a diagnosis of HLH. The peripheral blood showed evidence of phagocytosis by neutrophils, pseudo-Chediak-Higashi-like inclusions, blue-green inclusions, and intra-cytoplasmic vacuoles with shadowy appearance and cellular debris in the background. Acid-fast bacilli were demonstrated in the peripheral blood by Ziehl-Neelsen stain. His clinical condition gradually worsened with multi organ failure and fatality.

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"J BUON"[jour]; +50 new citations

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Tumor-Associated T-Lymphocytes and Macrophages are Decreased in Endometrioid Endometrial Carcinoma with MELF-Pattern Stromal Changes

Abstract

Microcystic, elongated, fragmented (MELF)-pattern is an unusual morphology of myometrial invasive front in endometrioid endometrial carcinoma (EA). The aim of the study was to investigate potential correlation between MELF-pattern and peritumoral inflammatory immune response. A total of 96 out of 368 patients were included in this study. CD3, CD20, CD57. CD68 and S100 markers were used for the detection of tumor-associated T-lymphocytes (TAT), tumor-associated B-lymphocytes (TAB), tumor-associated NK-lymphocytes (NK), tumor-associated macrophages and dendritic cells respectively. Mann-Whitney tests, receiver operating characteristic (ROC) curve analysis, and Spearman correlation were used as methods for statistical analyses. Odds ratio with 95% confidence interval (95% CI) was determined with the use of a logistic regression model. A p < 0.05 was considered statistically significant. Our results suggested that the number of CD3 and CD68 cells were significantly lower (p < 0.001) in cases of endometrioid carcinoma with MELF-pattern. A significant correlation between the presence of MELF-pattern and decrease of CD3 positive T-lymphocytes (r = 0.691; p < 0.001) was also observed. Additionally, we found an inverse correlation between the presence of MELF-pattern and TAM (r = 0.568; p = 0.001). Therefore, our data suggest that MELF-pattern may be associated with EA stroma fibrosis that contains immune cells infiltration and demonstrated a decrease in the number of TAT and TAM cells. This may indicate the poor clinical prognosis of this disease.

https://ift.tt/2mhtR8H