Clinical efficacy and safety of afatinib in the treatment of non-small-cell lung cancer in Chinese patients

http://ift.tt/2BwzIfz

Quantification of heart, pericardium, and left ventricular myocardium movements during the cardiac cycle for thoracic tumor radiotherapy

http://ift.tt/2nf8hT9

Clinical manifestations of pulmonary mucosa-associated lymphoid tissue lymphoma: single-center experience with 18 patients

http://ift.tt/2BvSWly

Self-Perceived Physical Attractiveness in Relation to Scars Among Adolescent and Young Adult Cancer Survivors: A Population-Based Study

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Australian Adolescents and Young Adults–Trends in Cancer Incidence, Mortality, and Survival Over Three Decades

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Self-Perceived Physical Attractiveness in Relation to Scars Among Adolescent and Young Adult Cancer Survivors: A Population-Based Study

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2DFdyxu

Australian Adolescents and Young Adults–Trends in Cancer Incidence, Mortality, and Survival Over Three Decades

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Nomogram for predicting survival in patients with pancreatic cancer

http://ift.tt/2DS6YDi

Simple surgical solution: scaphoid type congenital megalourethra

Description

Congenital megalourethra (CM) is an uncommon paediatric urogenital problem with less than 80 reported cases1 and may go ignored for years. It is defined as dilatation and elongation of the penile urethra associated with the deficiency of the corpora cavernosa and/or spongiosum. It may be of scaphoid or fusiform variety. However, surgery in most cases may be challenging.

A 10-year-old boy presented with the complaint of a swelling appearing on the under-surface of the penis during voiding since birth. This persisted even after micturation and had to be milked out post voiding. His urinary stream was of good calibre and normal volume. There was no associated history of urinary tract infection or obstruction. External genital examination was normal with bilateral descended testes, stretched penile length=4.5 cm, normal prepuce and normally positioned urethral meatus. However, dilatation of the dorsal penile shaft was observed during micturation. A retrograde cum voiding...

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Successful percutaneous drainage of pneumatoceles in an extremely low-birthweight infant

Pneumatoceles are thin-walled, air-filled cystic lesions developing within the lung parenchyma. It used to be a relatively common entity in the presurfactant era when preterm babies were ventilated at an unacceptably high positive pressure for respiratory distress syndrome. Pneumatocele formation is a very rare complication of pneumonia in neonates. We here report a case of extremely low-birthweight (ELBW) neonate who developed large bilateral pneumatoceles after staphylococcal pneumonia. Hereby, we present a case of an ELBW infant with bilateral massive pneumatoceles who underwent successful percutaneous catheter drainage to decompress these pneumatoceles.

http://ift.tt/2DGIe1n

Cryptococcal meningitis in a daily cannabis smoker without evidence of immunodeficiency

Cryptococcal meningitis is a life-threatening condition most commonly observed in immunocompromised individuals. We describe a daily cannabis smoker without evidence of immunodeficiency presenting with confirmed Cryptococcus neoformans meningitis. An investigation of cannabis samples from the patient's preferred dispensary demonstrated contamination with several varieties of Cryptococcus, including C. neoformans, and other opportunistic fungi. These findings raise concern regarding the safety of dispensary-grade cannabis, even in immunocompetent users.

http://ift.tt/2nfyujz

Hemiparesis in spontaneous spinal epidural haematoma: a potential stroke imitator

Spontaneous spinal epidural haematoma (SSEH) is a rare condition that requires urgent surgical intervention in order to prevent permanent neurological deficit. SSEH commonly presents as a paraparesis or tetraparesis. SSEH presenting as a hemiparesis is less common and in such situations, it can be mistaken for a cerebrovascular accident (CVA). Thrombolytic or anticoagulant treatment for CVA can potentially worsen the neurological deficit. We report one such case of SSEH misdiagnosed as a CVA. Treatment with tissue plasminogen activator led to worsening of his condition. On a subsequent cervical spine MRI, an epidural haematoma extending from C3 to C5 was detected and treated with laminectomy and evacuation. Surgical intervention led to significant improvement from American Spinal Injury Association Scale (ASIA) B to ASIA E. Presence of clinical features such as Horner's syndrome, Brown-Sequard syndrome and the absence of cranial nerve palsies in acute hemiparesis are indicative of SSEH rather than CVA.

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Desmoplastic fibroblastoma of the left upper arm

An elderly female patient presented to the clinic with a several-week history of a mass in her left upper arm that was tender to the touch. The mass was initially thought to be a schwannoma of the left radial nerve based on imaging and was surgically removed. The pathology report revealed an uncommon diagnosis of desmoplastic fibroblastoma.

http://ift.tt/2nhtDP1

Delayed diagnosis of dermal leiomyosarcoma mimicking keloid scar

A 43-year-old man developed an abnormal scar 6 months following excision of a leiomyoma from his left shoulder. The scar was elevated, irregular in shape, pink-red in colour, hard in consistency and it was extending beyond the margins of the original wound. A diagnosis of a keloid scar was considered and the patient was managed as such. He underwent a planned procedure for intralesional excision of the keloid scar. The histopathological examination showed a diagnosis of leiomyosarcoma. This case report presents a delayed diagnosis of dermal leiomyosarcoma mimicking a keloid scar. The patient subsequently underwent wider excision of the tumour with curative intention.

http://ift.tt/2DG9PzU

Neurogenic pulmonary oedema secondary to vertebral artery dissection while playing tennis

We present a case of a patient who developed vertebral artery dissection (VAD) while playing tennis and presented with neurogenic pulmonary oedema. The case highlights two important points: acute pulmonary oedema as an unusual presenting feature of VAD and VAD, an important cause of stroke in young people, as being associated with playing low-impact sports such as tennis. These associations, independent of each other, are under-recognised and can lead to a delay in diagnosis.

http://ift.tt/2nfBfRW

Dont put your foot in it: a case of talonavicular septic arthritis

We present the second documented case of primary septic arthritis of the talonavicular joint. This patient had a number of medical comorbidities, including chronic widespread pain including the ipsilateral limb, which made diagnosis an even greater challenge. Although a clinical diagnosis, joint fluid aspiration remains the gold standard. Prompt surgical drainage with adjuvant antibiotic treatment is recommended, and management requires a multidisciplinary team approach. The aim of treatment is to avoid the sequelae of joint destruction, pain and foot deformity.

http://ift.tt/2DIqoeI

Rare occurrence of eight-and-a-half syndrome as a clinically isolated syndrome

Eight-and-a-half syndrome is a rare condition that is described as a combination of one-and-a-half syndrome and an ipsilateral facial nucleus lesion. We present a clinical case of occurrence of eight-and-a-half syndrome that was caused by a demyelinating lesion in the dorsal pontine tegmentum. A 44-year-old man presented to the hospital with a subacute onset of horizontal diplopia and left-sided facial weakness. MRI revealed a T2 hyperintense lesion in his dorsal pons, which was consistent with a demyelinating pathology. Treatment with intravenous steroids showed significant improvement in his symptoms. In our case, it occurred due to a suspected demyelinating lesion that was this patient's first and only demyelinating event, leaving him with a diagnosis of clinically isolated syndrome. His responsiveness to steroids represents the first case report of an adult patient presenting with an eight-and-a-half syndrome secondary to a suspected demyelinating pathology.

http://ift.tt/2nh9Hvw

Sepsis Secondary to Bacteroides Fragilis Tubo-Ovarian Abscess Requiring Hysterectomy and Bilateral Salpingo-Oophorectomy

A 45-year-old, G0P0 premenopausal woman was admitted for investigation of right lower quadrant pain, fever, leucocytosis and right adnexal abscess on CT. She was started on intravenous antibiotics and underwent CT-guided percutaneous drainage from which Bacteroides fragilis was cultured. A few days later, she had an exploratory laparotomy with incision and drainage. Once stabilised, she was discharged on intravenous antibiotics. She was followed outpatient and subsequent imaging demonstrated significant improvement of the abscess. After being asymptomatic for 3 months, she again presented to the emergency department with right lower quadrant abdominal pain, fever and leucocytosis. Two days later, she underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy. She made a full recovery and began treatment with a herbal oestrogen derivative to prevent early menopause.

http://ift.tt/2DI9gpa

Clostridium difficile enteritis: diffuse small bowel radiological changes in a patient with abdominal sepsis

While imaging appearances of pseudomembranous colitis are commonly recognised, radiological manifestations of Clostridium difficile-associated enteritis are poorly understood which, combined with the rarity of this infection involving small bowel, makes establishing the correct diagnosis challenging. Therefore, in order to encourage awareness of readers, we present a case of C. difficile enteritis that manifested as abdominal sepsis complicating the postoperative period in a middle-aged woman with fistulating Crohn's disease and defunctioning ileostomy. Radiological appearances are described based on three consecutive CT studies performed 5 days prior to onset of symptoms, during the peak of enteritis, corresponding with the patient's clinical deterioration, and also 35 days later following treatment and resolution.

http://ift.tt/2ng6rkk

Emergency percutaneous transtracheal jet ventilation in a hypoxic cardiopulmonary resuscitation setting: a life-saving rescue technique

(Un)anticipated difficult airway remains a challenge in anaesthesia. Percutaneous transtracheal jet ventilation has been shown to be an adequate technique for temporary oxygenation and ventilation and has been described as an acknowledged method in emergency settings of an unanticipated difficult airway. These emergency settings can be considered as low incidence high-risk situations. Both technical and non-technical skills should be trained regularly as education and simulation continues to play an important factor in patient safety. Furthermore, postoperative laryngeal oedema due to altered lymphatic drainage patterns must be considered as a possible mechanism of an upper airway obstruction in combination with a history of neck dissection and radiotherapy.

http://ift.tt/2nfCrVC

Perimesencephalic and sulcal subarachnoid haemorrhage: an interesting presentation of posterior reversible encephalopathy syndrome

Description

A 38-year-old man with hypertension presented with sudden-onset headache and vomiting. He was irritable and had a blood pressure of 180/120 mm Hg. There were no meningeal signs or focal neurological deficits. His optic fundi were normal. Initial evaluation with CT of the brain showed subarachnoid haemorrhage (SAH) in the right parasagittal sulcal region (figure 1A) and the left perimesencephalic cistern (figure 1B). A CT angiogram (CTA) followed by a digital subtraction angiogram (DSA) ruled out aneurysms (figure 1C–F). The venous phase of DSA (figure 1G) and magnetic resonance (MR) venogram (figure 1H,I) were normal. MRI of the brain (figure 2) showed hyperintense lesions in the bilateral parieto-occipital regions and the basal ganglia suggesting posterior reversible encephalopathy syndrome (PRES). He was managed with antihypertensives and made a gradual and complete recovery.

Figure 1

CT...

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Fluctuating hypercalcaemia caused by cavitary Mycobacterium bovis pulmonary infection

Hypercalcaemia occurs in many granulomatous diseases. Among them, sarcoidosis and tuberculosis are the most common causes. Other causes include berylliosis, coccidioidomycosis, histoplasmosis, Crohn's disease, silicone-induced granulomas, cat-scratch disease, Wegener's granulomatosis and Pneumocystis carinii pneumonia. Hypercalcaemia in granulomatous disease occurs as a consequence of dysregulated production of 1,25-(OH)2 D3 (calcitriol) by activated macrophages in granulomas. Hypercalcaemia in patients with Mycobacterium tuberculosis infection has been reported in 0%–28% of cases. Uncultured bronchoalveolar lavage cells from patients with M. tuberculosis produce greater amounts of calcitriol compared with controls. Although Nayar et al described hypercalcaemia in a case of sepsis associated with intravesical Bacille Calmette Guerin therapy, there are no published reports describing hypercalcaemia in patients with pulmonary M. bovis infection. We describe a patient with M. bovis cavitary pulmonary infection with sustained hypercalcaemia that fluctuated and recurred repeatedly over the course of therapy, ultimately culminating in normalisation of serum calcium when therapy had led to cure. Treatment consisted of antituberculous therapy, oral corticosteroids and intravenous bisphosphonates with a favourable outcome.

http://ift.tt/2Gjq8Aa

Spontaneous calf haematoma in severe dengue

We report a case of spontaneous calf muscle haematoma, formed during the recovery phase of dengue haemorrhagic fever, which, to the best of our knowledge, has never been encountered before. A 45-year-old man presented with features of severe dengue and got admitted to our intensive care unit. He was treated with intravenous fluid therapy and supportive measures, and gradually improved, initially. However, during the recovery phase, he suddenly developed painful left calf, which was found tender, hot and swollen on physical examination. Colour Doppler ultrasound revealed left calf haematoma. As the patient rapidly developed local compartmental syndrome, surgical evacuation of the haematoma followed by urgent fasciotomy was performed. He recovered without further complication and was discharged home. At follow-up after 2 months, he remained well.

http://ift.tt/2rHgX9s

Acute retinal detachment induced by the Valsalva manoeuvre in morning glory disc anomaly

We present a case in which a large, bullous, predominantly inferior, serous retinal detachment developed acutely after the Valsalva manoeuvre (from a coughing fit) in an eye with morning glory disc anomaly. We postulate that a rapid alteration in intracranial pressure was transmitted through the cavitary disc defect. This allowed a sudden influx of cerebrospinal fluid and/or liquefied vitreous into the subretinal space. This previously unreported case provides important evidence for the role of intracranial pressure fluctuations in the pathogenesis of macular schisis and neurosensory detachment secondary to optic disc cavitations.

http://ift.tt/2Gljnhf

Oculocutaneous albinism with iridofundal coloboma

Description

A 20-year-old woman presented to the retina clinic with complaints of diminution of vision, photophobia and involuntary movement of both eyes since birth. The patient had light-coloured skin complexion along with golden hair. Best corrected visual acuity was 1/60 and 4/60 in the right and left eyes, respectively. Ocular examination revealed manifest nystagmus, but there was no evidence of squint or head posture. The anterior segment had clear cornea and lens, with colobomatous light-coloured iris. Fundus examination in the right eye showed diffusely hypopigmented fundus with a large, well-defined excavated area along the inferior and nasal quadrant, extending well above the optic disc and the macula, suggestive of type I iridofundal coloboma (figure 1). Similarly, in the left eye, there was diffuse hypopigmentation except at the macula. Retinal and choroidal vessels were well appreciated along with their drainage into the vortex veins (figure 2)....

http://ift.tt/2rLRVGt

Secondary Omental Infarction in a Patient with a Hypercoagulable State

Omental infarction is a rare cause of acute and non-specific abdominal pain. We report a case of a 46-year-old man who presented to the emergency room with right upper quadrant cramping pain that was of sudden onset. The patient's presentation was later diagnosed as an omental infarction, by an abdominal CT. After extensive work-up, it was revealed that the cause of the patient's omental infarction was secondary to a hypercoagulable state caused by antiphospholipid syndrome, based on his thrombophilia work-up. The patient was successfully managed conservatively and was started on lifelong anticoagulation. The patient was followed up with an abdominal CT after 2 months into therapy, which showed a decrease in the size of the omental infarction and a significant improvement in his state.

http://ift.tt/2GkL9KS

Chronic reactive arthritis associated with prostatitis caused by Neisseria meningitidis

Description

A 29-year-old man presented with a 10-year history of pain in his right ankle. The ankle was tender and swollen, and there was Achilles tendinitis. He had no complaints of buttock pain, abdominal pain, dysuria or a feeling of incomplete voiding. Skin examination was normal. Laboratory investigations revealed a leucocyte count of 6.0x10⁹/L and a serum C reactive protein level of 5.21 mg/dL. Liver and renal function tests were normal. Rheumatoid factor, anticyclic citrullinated peptide antibody and antinuclear antibody were negative. Urinalysis was positive for occult blood, but there was no leucocyturia. Locus B human leukocyte antigen (HLA) typing was positive for B27. Plain radiography of the right ankle joint showed narrowing of the subtalar joint space and heel spurs on the plantar aspect of the calcaneus (figure 1). Contrast-enhanced CT scans demonstrated enhanced lesions in the peripheral zone of the prostate (figure 2). Culture...

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Strangulated Spiegels hernia mimicking ischaemic colitis: endoscopic diagnosis of a rare surgical emergency

Description

An 84-year-old man was referred to the emergency department with a 2-day history of colicky abdominal pain in the left lower quadrant, bloody diarrhoea and abdominal distension. Nausea and two episodes of watery vomiting were reported as well. Past medical history was remarkable for arterial hypertension, dyslipidaemia and ischaemic stroke, for which he was taking lisinopril, hydrochlorothiazide, simvastatin and acetylsalicylic acid. Surgical background included laparotomy for appendectomy and appendicular abscess drainage 8 years before.

Physical examination showed stable vital signs and a distended abdomen, with tenderness in the left lower abdominal quadrant, but no signs of peritoneal irritation. An obvious, but reducible, abdominal wall hernia was palpable in the same location. The remaining exam was unremarkable.

Laboratory results revealed mild anaemia (haemoglobin—12.7 g/dL) and leukocytosis (white cell count—11.7x10⁹/L), acute kidney injury (creatinine—2.1 mg/dL) and elevated C reactive protein (298 mg/L). Liver function tests, electrolyte panel, amylase and lactate dehydrogenase were within...

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A phase II study of tipifarnib and gemcitabine in metastatic breast cancer

Summary

Background Tipifarnib is an orally active, competitive inhibitor of farnesyltransferase which has shown encouraging signs of activity either alone or when combined with other agents. Clinical studies of tipifarnib in combination with anti-estrogen therapy have yielded disappointing results. In contrast, tipifarnib appears to be synergistic in combination with anthracycline based chemotherapy. Here we report the results of the first prospective phase II trial evaluating the efficacy of the novel combination of tipifarnib and gemcitabine in the treatment of metastatic breast cancer. Patients and Methods 30 postmenopausal women with metastatic breast cancer were treated on a 21-day cycle with tipifarnib 300 mg PO twice daily from days 1 through 14. Gemcitabine was administered intravenously at a dose of 1000 mg/m² on days 1 and 8. Patients were treated until disease progression or unacceptable toxicity. Results There was one complete response and four partial responses yielding an objective response rate of 16.7%. Median progression-free survival and overall survival was 2.5 months (95% confidence interval: 1.6–5.7 months) and 13.1 months (95% confidence interval: 9.1–20.6 months), respectively. 40% of patients experienced grade 4 neutropenia in this study. Conclusion The combination of tipifarnib and gemcitabine is not well tolerated with high rates of myelosuppression and is not more effective than gemcitabine monotherapy in the treatment of metastatic breast cancer.

http://ift.tt/2ngW6oe

A phase II study of tipifarnib and gemcitabine in metastatic breast cancer

Summary

Background Tipifarnib is an orally active, competitive inhibitor of farnesyltransferase which has shown encouraging signs of activity either alone or when combined with other agents. Clinical studies of tipifarnib in combination with anti-estrogen therapy have yielded disappointing results. In contrast, tipifarnib appears to be synergistic in combination with anthracycline based chemotherapy. Here we report the results of the first prospective phase II trial evaluating the efficacy of the novel combination of tipifarnib and gemcitabine in the treatment of metastatic breast cancer. Patients and Methods 30 postmenopausal women with metastatic breast cancer were treated on a 21-day cycle with tipifarnib 300 mg PO twice daily from days 1 through 14. Gemcitabine was administered intravenously at a dose of 1000 mg/m² on days 1 and 8. Patients were treated until disease progression or unacceptable toxicity. Results There was one complete response and four partial responses yielding an objective response rate of 16.7%. Median progression-free survival and overall survival was 2.5 months (95% confidence interval: 1.6–5.7 months) and 13.1 months (95% confidence interval: 9.1–20.6 months), respectively. 40% of patients experienced grade 4 neutropenia in this study. Conclusion The combination of tipifarnib and gemcitabine is not well tolerated with high rates of myelosuppression and is not more effective than gemcitabine monotherapy in the treatment of metastatic breast cancer.

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Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports

Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrat...

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Reversal of end-stage heart failure in juvenile hemochromatosis with iron chelation therapy: a case report

Juvenile hemochromatosis is the most severe form of iron overloading phenotype. Although rare, it should be suspected in patients who present with hypogonadotropic hypogonadism, diabetes mellitus, or cardiomyo...

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Enhancer-Driven Gene Expression Changes Facilitate Metastasis [Research Watch]

Altered enhancer activity allows for dynamic gene expression to promote osteosarcoma metastasis.

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Blood Monocyte Frequency May Be a Biomarker for Response to Anti-PD-1 [Research Watch]

CD14⁺CD16^–HLA-DR^hi monocyte frequency was linked to response to anti–PD-1 in patients with melanoma.

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Chromosomal Instability Drives Metastasis Independent of Aneuploidy [Research Watch]

Chromosomal instability (CIN) promotes metastasis with little effect on primary tumor growth.

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Dimerization Is Critical for the Functions of Wild-type and Mutant KRAS [Research Watch]

Wild-type KRAS increases survival and resistance to MEK inhibitors in KRAS-mutant lung cancer cells.

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Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1 negative human lung cancers

Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non-small-cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2. Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x and HHLA2 on human T cell proliferation and cytokine production were investigated. Results: PD-L1 expression was identified in 25% and 31% of tumors in the discovery and validation cohorts, and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68%, while HHLA2 was positive in 61% and 64% of tumors in the two sets. The co-expression of PD-L1 with B7x or HHLA2 was infrequent, 6% and 3%. The majority (78%) of PD-L1 negative cases expressed B7x, HHLA2 or both. The triple positive group had more TIL infiltration than the triple negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells. Conclusion: The majority of PD-L1 negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1 negative tumors deserves to be explored to provide the rationale for an effective immunotherapy strategy in these tumors.

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The strategy of PIKing a target: What is AKTually most effective?

Breast and gynecological cancers harboring PIK3CA mutations showed no significant responses to AZD5363, a pan-AKT catalytic inhibitor, in contrast with previous in vitro data showing activity of the drug in this subset of cancers. These results raise the question on how to select the most accurate predictive biomarkers of response.

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Immune biomarkers predictive for disease-free survival with adjuvant sunitinib in high-risk locoregional renal cell carcinoma: from randomized phase III S-TRAC study

Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma in the S-TRAC trial (ClinicalTrials.gov number, NCT00375674). A prospectively-designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit. Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan-Meier method. For biomarkers with predictive potential, Receiver Operating Characteristics curves were generated. Results: Baseline characteristics were similar in patients with (n=191) and without (n=419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8+ T-cell density ≥ versus < median (median [95% CI], not reached [6.83-not reached] vs. 3.47 years [1.73-not reached]; hazard ratio 0.40 [95% CI, 0.20-0.81]; P=0.009) treated with sunitinib (n=101), but not with placebo (n=90). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1+ versus PD-L1- tumors (hazard ratio 1.75; P=0.103). Among all patients with PD-L1+ tumors, DFS was numerically longer with sunitinib versus placebo (hazard ratio 0.58; P=0.175). Conclusions: Greater CD8+ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic renal cell carcinoma should also be further explored.

http://ift.tt/2FnhQGp

Small Cell Neuroendocrine Tumors: Cell State Trumps the Oncogenic Driver.

Small cell neuroendocrine cancers often originate in the lung, but can also arise in the bladder or prostate. Phenotypically, small cell carcinoma of the bladder (SCCB) shares many similarities with small cell lung cancer (SCLC). It is unknown whether SCCB and SCLC share common genetic driver mutations.

http://ift.tt/2DOQzPR

Circulating tumor cells with stem-like phenotypes for diagnosis, prognosis and therapeutic response evaluation in hepatocellular carcinoma

Purpose: In present study, we assessed the clinical value of circulating tumor cells (CTCs) with stem-like phenotypes for diagnosis, prognosis and surveillance in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by an optimized QPCR-based detection platform. Experimental Design:Differing subsets of CTCs were investigated, and a multimarker diagnostic CTC panel was constructed in a multicenter-patient study with independent validation (total n=1006), including healthy individuals, patients with chronic hepatitis B infection (CHB), liver cirrhosis (LC), benign hepatic lesion (BHL) and HBV-related HCC, with area under the receiver operating characteristic curve (AUC-ROC) reflecting diagnostic accuracy. The role of CTC panel in treatment response surveillance and its prognostic significance were further investigated. Results: The AUC of CTC panel was 0.88 in training set [sensitivity=72·5%, specificity=95.0%, positive predictive value (PPV) =92.4, negative predictive value (NPV)=77.8] and 0.93 in validation set (sensitivity=82·1%; specificity=94.2%, PPV=89.9, NPV=89.3). This panel performed equally well in detecting early-stage and α-fetoprotein (AFP)-negative HCC, as well as differentiating HCC from CHB, LC and BHL. The CTC load was decreased significantly after tumor resection, and patients with persistently high CTC load showed a propensity of tumor recurrence after surgery. The prognostic significance of CTC panel in predicting tumor recurrence was further confirmed (training: HR=2.692, 95% CI, 1.617-4.483, P<0.001; validation: HR=3.127, 95% CI, 1.360-7.190, P=0.007). Conclusions: Our CTC panel showed high sensitivity and specificity in HCC diagnosis and could be a real-time parameter for risk prediction and treatment monitoring, enabling early decision-making to tailor effective antitumor strategies.

http://ift.tt/2Fmp90Z

Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1 negative human lung cancers

Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non-small-cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2. Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x and HHLA2 on human T cell proliferation and cytokine production were investigated. Results: PD-L1 expression was identified in 25% and 31% of tumors in the discovery and validation cohorts, and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68%, while HHLA2 was positive in 61% and 64% of tumors in the two sets. The co-expression of PD-L1 with B7x or HHLA2 was infrequent, 6% and 3%. The majority (78%) of PD-L1 negative cases expressed B7x, HHLA2 or both. The triple positive group had more TIL infiltration than the triple negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells. Conclusion: The majority of PD-L1 negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1 negative tumors deserves to be explored to provide the rationale for an effective immunotherapy strategy in these tumors.

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The strategy of PIKing a target: What is AKTually most effective?

Breast and gynecological cancers harboring PIK3CA mutations showed no significant responses to AZD5363, a pan-AKT catalytic inhibitor, in contrast with previous in vitro data showing activity of the drug in this subset of cancers. These results raise the question on how to select the most accurate predictive biomarkers of response.

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Immune biomarkers predictive for disease-free survival with adjuvant sunitinib in high-risk locoregional renal cell carcinoma: from randomized phase III S-TRAC study

Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma in the S-TRAC trial (ClinicalTrials.gov number, NCT00375674). A prospectively-designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit. Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan-Meier method. For biomarkers with predictive potential, Receiver Operating Characteristics curves were generated. Results: Baseline characteristics were similar in patients with (n=191) and without (n=419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8+ T-cell density ≥ versus < median (median [95% CI], not reached [6.83-not reached] vs. 3.47 years [1.73-not reached]; hazard ratio 0.40 [95% CI, 0.20-0.81]; P=0.009) treated with sunitinib (n=101), but not with placebo (n=90). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1+ versus PD-L1- tumors (hazard ratio 1.75; P=0.103). Among all patients with PD-L1+ tumors, DFS was numerically longer with sunitinib versus placebo (hazard ratio 0.58; P=0.175). Conclusions: Greater CD8+ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic renal cell carcinoma should also be further explored.

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Small Cell Neuroendocrine Tumors: Cell State Trumps the Oncogenic Driver.

Small cell neuroendocrine cancers often originate in the lung, but can also arise in the bladder or prostate. Phenotypically, small cell carcinoma of the bladder (SCCB) shares many similarities with small cell lung cancer (SCLC). It is unknown whether SCCB and SCLC share common genetic driver mutations.

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Circulating tumor cells with stem-like phenotypes for diagnosis, prognosis and therapeutic response evaluation in hepatocellular carcinoma

Purpose: In present study, we assessed the clinical value of circulating tumor cells (CTCs) with stem-like phenotypes for diagnosis, prognosis and surveillance in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by an optimized QPCR-based detection platform. Experimental Design:Differing subsets of CTCs were investigated, and a multimarker diagnostic CTC panel was constructed in a multicenter-patient study with independent validation (total n=1006), including healthy individuals, patients with chronic hepatitis B infection (CHB), liver cirrhosis (LC), benign hepatic lesion (BHL) and HBV-related HCC, with area under the receiver operating characteristic curve (AUC-ROC) reflecting diagnostic accuracy. The role of CTC panel in treatment response surveillance and its prognostic significance were further investigated. Results: The AUC of CTC panel was 0.88 in training set [sensitivity=72·5%, specificity=95.0%, positive predictive value (PPV) =92.4, negative predictive value (NPV)=77.8] and 0.93 in validation set (sensitivity=82·1%; specificity=94.2%, PPV=89.9, NPV=89.3). This panel performed equally well in detecting early-stage and α-fetoprotein (AFP)-negative HCC, as well as differentiating HCC from CHB, LC and BHL. The CTC load was decreased significantly after tumor resection, and patients with persistently high CTC load showed a propensity of tumor recurrence after surgery. The prognostic significance of CTC panel in predicting tumor recurrence was further confirmed (training: HR=2.692, 95% CI, 1.617-4.483, P<0.001; validation: HR=3.127, 95% CI, 1.360-7.190, P=0.007). Conclusions: Our CTC panel showed high sensitivity and specificity in HCC diagnosis and could be a real-time parameter for risk prediction and treatment monitoring, enabling early decision-making to tailor effective antitumor strategies.

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RNF6 promotes colorectal cancer by activating the Wnt/{beta}-catenin pathway via ubiquitination of TLE3

Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer (CRC). Previous whole-genome sequencing of CRC clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we show that RNF6 is upregulated in 73.5% (147/200) of CRC patients, and was positively associated with RNF6 gene amplification. Further, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of CRC patients. RNF6 promoted cell growth, cell cycle progression, and epithelial-to-mesenchymal transition in CRC cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis.

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MicroRNA-508 defines the stem-like/mesenchymal subtype in colorectal cancer

Colorectal cancer (CRC) includes an invasive stem-like/mesenchymal subtype but its genetic drivers, functional and clinical relevance are uncharacterized. Here we report the definition of an altered microRNA (miR) signature defining this subtype which includes a major genomic loss of miR-508. Mechanistic investigations showed that this microRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, BMI1 and BMI1. Loss of miR-508 in CRC was associated with upregulation of the novel hypoxia-induced long non-coding RNA AK000053. Ectopic expression of miR-508 in CRC cells blunted epithelial-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical CRC specimens, expression of miRNA-508 negatively correlated with stemness and EMT-associated gene expression and inversely correlated with patient survival. Overall, our results showed that miRNA-508 is a key functional determinant of the stem-like/mesenchymal CRC subtype and a candidate therapeutic target for its treatment.

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Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer

Metformin is a broadlyprescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer (OC) by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α (AMPKα) and subsequently suppressed hypoxia-inducible factor-α (HIF-1α), which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with OC, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+MDSC and a concomitant increase in the antitumor activities of circulating CD8+T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in OC patients.

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Forkhead box F2 suppresses gastric cancer through a novel FOXF2-IRF2BPL-{beta}-catenin signaling axis

DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of GC. Using genome-wide methylation studies we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in GC. We then investigated the functional significance and clinical implication of FOXF2 in GC. FOXF2 was silenced in GC cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G1-S cell cycle transition, induced apoptosis of GC cell lines and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2 binding protein like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early stage GC patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for GC patients.

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RNF6 promotes colorectal cancer by activating the Wnt/{beta}-catenin pathway via ubiquitination of TLE3

Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer (CRC). Previous whole-genome sequencing of CRC clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we show that RNF6 is upregulated in 73.5% (147/200) of CRC patients, and was positively associated with RNF6 gene amplification. Further, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of CRC patients. RNF6 promoted cell growth, cell cycle progression, and epithelial-to-mesenchymal transition in CRC cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis.

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MicroRNA-508 defines the stem-like/mesenchymal subtype in colorectal cancer

Colorectal cancer (CRC) includes an invasive stem-like/mesenchymal subtype but its genetic drivers, functional and clinical relevance are uncharacterized. Here we report the definition of an altered microRNA (miR) signature defining this subtype which includes a major genomic loss of miR-508. Mechanistic investigations showed that this microRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, BMI1 and BMI1. Loss of miR-508 in CRC was associated with upregulation of the novel hypoxia-induced long non-coding RNA AK000053. Ectopic expression of miR-508 in CRC cells blunted epithelial-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical CRC specimens, expression of miRNA-508 negatively correlated with stemness and EMT-associated gene expression and inversely correlated with patient survival. Overall, our results showed that miRNA-508 is a key functional determinant of the stem-like/mesenchymal CRC subtype and a candidate therapeutic target for its treatment.

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Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer

Metformin is a broadlyprescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer (OC) by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α (AMPKα) and subsequently suppressed hypoxia-inducible factor-α (HIF-1α), which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with OC, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+MDSC and a concomitant increase in the antitumor activities of circulating CD8+T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in OC patients.

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Forkhead box F2 suppresses gastric cancer through a novel FOXF2-IRF2BPL-{beta}-catenin signaling axis

DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of GC. Using genome-wide methylation studies we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in GC. We then investigated the functional significance and clinical implication of FOXF2 in GC. FOXF2 was silenced in GC cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G1-S cell cycle transition, induced apoptosis of GC cell lines and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2 binding protein like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early stage GC patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for GC patients.

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Comparative Evaluation of Using NOTA and DOTA Derivatives as Bifunctional Chelating Agents in the Preparation of 68Ga-Labeled Porphyrin: Impact on Pharmacokinetics and Tumor Uptake in a Mouse Model

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Cancers, Vol. 10, Pages 33: The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

Cancers, Vol. 10, Pages 33: The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

Cancers doi: 10.3390/cancers10020033

Authors: Sandra Valle Laura Martin-Hijano Sonia Alcalá Marta Alonso-Nocelo Bruno Sainz Jr.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (&lt;7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.

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Cancers, Vol. 10, Pages 33: The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

Cancers, Vol. 10, Pages 33: The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

Cancers doi: 10.3390/cancers10020033

Authors: Sandra Valle Laura Martin-Hijano Sonia Alcalá Marta Alonso-Nocelo Bruno Sainz Jr.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (&lt;7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.

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Computed tomography and magnetic resonance imaging evaluation of pelvic lymph node metastasis in bladder cancer

Accurate evaluation of lymph node metastasis in bladder cancer (BCa) is important for disease staging, treatment selection, and prognosis prediction. In this study, we aimed to evaluate the diagnostic accuracy...

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Computed tomography and magnetic resonance imaging evaluation of pelvic lymph node metastasis in bladder cancer

Accurate evaluation of lymph node metastasis in bladder cancer (BCa) is important for disease staging, treatment selection, and prognosis prediction. In this study, we aimed to evaluate the diagnostic accuracy...

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Long-term outcomes of rituximab, temozolomide and high-dose methotrexate without consolidation therapy for lymphoma involving the CNS

International Journal of Hematologic Oncology, Ahead of Print.


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Long-term outcomes of rituximab, temozolomide and high-dose methotrexate without consolidation therapy for lymphoma involving the CNS

International Journal of Hematologic Oncology, Ahead of Print.


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Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential

Publication date: Available online 25 January 2018
Source:Cell Stem Cell
Author(s): Robert N. Judson, Marco Quarta, Menno J. Oudhoff, Hesham Soliman, Lin Yi, Chih Kai Chang, Gloria Loi, Ryan Vander Werff, Alissa Cait, Mark Hamer, Justin Blonigan, Patrick Paine, Linda T.N. Doan, Elena Groppa, WenJun He, Le Su, Regan H. Zhang, Peter Xu, Christine Eisner, Marcela Low, Ingrid Barta, Coral-Ann B. Lewis, Colby Zaph, Mohammad M. Karimi, Thomas A. Rando, Fabio M. Rossi
The development of cell therapy for repairing damaged or diseased skeletal muscle has been hindered by the inability to significantly expand immature, transplantable myogenic stem cells (MuSCs) in culture. To overcome this limitation, a deeper understanding of the mechanisms regulating the transition between activated, proliferating MuSCs and differentiation-primed, poorly engrafting progenitors is needed. Here, we show that methyltransferase Setd7 facilitates such transition by regulating the nuclear accumulation of β-catenin in proliferating MuSCs. Genetic or pharmacological inhibition of Setd7 promotes in vitro expansion of MuSCs and increases the yield of primary myogenic cell cultures. Upon transplantation, both mouse and human MuSCs expanded with a Setd7 small-molecule inhibitor are better able to repopulate the satellite cell niche, and treated mouse MuSCs show enhanced therapeutic potential in preclinical models of muscular dystrophy. Thus, Setd7 inhibition may help bypass a key obstacle in the translation of cell therapy for muscle disease.

Graphical abstract

Teaser

Judson et al. show that lysine-methyltransferase Setd7 acts cytoplasmically to regulate the differentiation of skeletal muscle stem cells (MuSCs) by priming β-catenin for nuclear import. Pharmacological inhibition of Setd7 can provide a strategy to enhance the in vitro expansion and transplantation potential of murine and human MuSCs.


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Durvalumab verbessert die Prognose beim lokal fortgeschrittenen nicht-kleinzelligen Bronchialkarzinom nach definitiver Radiochemotherapie

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Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma

Abstract

Background

Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma.

Methods

To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction.

Results

Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. Decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin.

Conclusions

Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma.

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Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma

Abstract

Background

Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma.

Methods

To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction.

Results

Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. Decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin.

Conclusions

Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma.

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Is ERAS effective and safe in laparoscopic gastrectomy for gastric carcinoma? A meta-analysis

Abstract

Background

It is still unclear whether enhanced recovery after surgery is effective and safe in laparoscopic gastrectomy for gastric carcinoma.

Methods

Cochrane library databases, Medline, Embase, and Pubmed were searched from January 1, 1986, to December 31, 2016. Randomized controlled trials (RCTs) comparing fast-track recovery with conventional recovery strategies in laparoscopic radical gastrectomy for gastric carcinoma were included. The main outcomes measured were postoperative hospital stay, time to first flatus, hospital charge, and overall complication rate.

Results

Six RCTs with 400 patients were included in this study. Fast-track surgery has shorter postoperative hospital stays (weighted mean difference (WMD) − 2.65; 95% CI, − 4.01 to − 1.29, z = 3.82, P < 0.01) and less hospitalization expenditure (WMD − 523.43; 95% CI, − 799.79 to − 247.06, z = 3.71, P < 0.01) than conventional recovery strategies. There was no significant difference with respect to duration to first flatus (WMD − 17.72; 95% CI, − 39.46–4.02, z = 1.60, P = 0.11) and complication rate (OR 1.57; 95% CI, 0.82–2.98, z = 1.37, P = 0.17).

Conclusions

Enhanced recovery after surgery is effective and safe and is thus recommended in laparoscopic radical gastrectomy for gastric carcinoma.

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Is ERAS effective and safe in laparoscopic gastrectomy for gastric carcinoma? A meta-analysis

Abstract

Background

It is still unclear whether enhanced recovery after surgery is effective and safe in laparoscopic gastrectomy for gastric carcinoma.

Methods

Cochrane library databases, Medline, Embase, and Pubmed were searched from January 1, 1986, to December 31, 2016. Randomized controlled trials (RCTs) comparing fast-track recovery with conventional recovery strategies in laparoscopic radical gastrectomy for gastric carcinoma were included. The main outcomes measured were postoperative hospital stay, time to first flatus, hospital charge, and overall complication rate.

Results

Six RCTs with 400 patients were included in this study. Fast-track surgery has shorter postoperative hospital stays (weighted mean difference (WMD) − 2.65; 95% CI, − 4.01 to − 1.29, z = 3.82, P < 0.01) and less hospitalization expenditure (WMD − 523.43; 95% CI, − 799.79 to − 247.06, z = 3.71, P < 0.01) than conventional recovery strategies. There was no significant difference with respect to duration to first flatus (WMD − 17.72; 95% CI, − 39.46–4.02, z = 1.60, P = 0.11) and complication rate (OR 1.57; 95% CI, 0.82–2.98, z = 1.37, P = 0.17).

Conclusions

Enhanced recovery after surgery is effective and safe and is thus recommended in laparoscopic radical gastrectomy for gastric carcinoma.

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Renal sympathetic nerve activity after catheter-based renal denervation

Abstract

Background

Catheter-based renal sympathetic denervation (RDN) has been considered a potential treatment for therapy resistant hypertension (RHT). However, in a randomized placebo-controlled trial, RDN did not lead to a substantial blood pressure (BP) reduction. We hypothesized that variation in the reported RDN efficacy might be explained by incomplete nerve disruption as assessed by renal ¹²³I–meta-iodobenzylguanidine (¹²³I–mIBG) scintigraphy.

Methods

In 21 RHT patients (median age 60 years), we performed ¹²³I–mIBG scintigraphy before and 6 weeks after RDN. Additionally, we assessed changes in BP (24 h day, night, and average), plasma- and urinary-catecholamines and plasma renin activity (PRA) before and after RDN. Planar scintigraphy was performed at 15 min and 4 h after ¹²³I–mIBG administration. The ratio of the mean renal (specific) counts vs. muscle (non-specific) counts represented ¹²³I–mIBG uptake. Renal ¹²³I–mIBG washout was calculated between 15 min and 4 h.

Results

After RDN office-based systolic BP decreased from 172 to 153 mmHg (p = 0.036), while diastolic office BP (p = 0.531), mean 24 h systolic and diastolic BP (p = 0.602, p = 0.369, respectively), PRA (p = 0.409) and plasma catecholamines (p = 0.324) did not significantly change post-RDN. Following RDN, ¹²³I–mIBG renal uptake at 15 min was 3.47 (IQR 2.26–5.53) compared to 3.08 (IQR 2.79–4.95) before RDN (p = 0.289). Renal ¹²³I–mIBG washout did not change post-RDN (p = 0.230). In addition, there was no significant correlation between the number of denervations and the renal ¹²³I–mIBG parameters.

Conclusions

No changes were observed in renal ¹²³I–mIBG uptake or washout at 6 weeks post-RDN. These observations support incomplete renal denervation as a possible explanation for the lack of RDN efficacy.

http://ift.tt/2naAFWI

Renal sympathetic nerve activity after catheter-based renal denervation

Abstract

Background

Catheter-based renal sympathetic denervation (RDN) has been considered a potential treatment for therapy resistant hypertension (RHT). However, in a randomized placebo-controlled trial, RDN did not lead to a substantial blood pressure (BP) reduction. We hypothesized that variation in the reported RDN efficacy might be explained by incomplete nerve disruption as assessed by renal ¹²³I–meta-iodobenzylguanidine (¹²³I–mIBG) scintigraphy.

Methods

In 21 RHT patients (median age 60 years), we performed ¹²³I–mIBG scintigraphy before and 6 weeks after RDN. Additionally, we assessed changes in BP (24 h day, night, and average), plasma- and urinary-catecholamines and plasma renin activity (PRA) before and after RDN. Planar scintigraphy was performed at 15 min and 4 h after ¹²³I–mIBG administration. The ratio of the mean renal (specific) counts vs. muscle (non-specific) counts represented ¹²³I–mIBG uptake. Renal ¹²³I–mIBG washout was calculated between 15 min and 4 h.

Results

After RDN office-based systolic BP decreased from 172 to 153 mmHg (p = 0.036), while diastolic office BP (p = 0.531), mean 24 h systolic and diastolic BP (p = 0.602, p = 0.369, respectively), PRA (p = 0.409) and plasma catecholamines (p = 0.324) did not significantly change post-RDN. Following RDN, ¹²³I–mIBG renal uptake at 15 min was 3.47 (IQR 2.26–5.53) compared to 3.08 (IQR 2.79–4.95) before RDN (p = 0.289). Renal ¹²³I–mIBG washout did not change post-RDN (p = 0.230). In addition, there was no significant correlation between the number of denervations and the renal ¹²³I–mIBG parameters.

Conclusions

No changes were observed in renal ¹²³I–mIBG uptake or washout at 6 weeks post-RDN. These observations support incomplete renal denervation as a possible explanation for the lack of RDN efficacy.

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Study Identifies Potential Cause of Hearing Loss from Cisplatin

A new study has found the commonly used chemotherapy drug cisplatin is retained in the inner ear of mice and humans for long periods. The finding may explain why many patients treated with the drug develop hearing loss and could point toward potential ways to prevent it.

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Study Identifies Potential Cause of Hearing Loss from Cisplatin

A new study has found the commonly used chemotherapy drug cisplatin is retained in the inner ear of mice and humans for long periods. The finding may explain why many patients treated with the drug develop hearing loss and could point toward potential ways to prevent it.

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[Europe and Japan alliance for clinical research in oncology].

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[Europe and Japan alliance for clinical research in oncology].

Bull Cancer. 2018 Jan 20;:

Authors: Evrard S

PMID: 29366499 [PubMed - as supplied by publisher]

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PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway.

Related Articles

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway.

Cancer Biol Ther. 2018 Jan 25;:1-8

Authors: Ibrahim S, Li G, Hu F, Hou Z, Chen Q, Li G, Luo X, Hu J, Feng Y

Abstract
Phosphoinositide-3-kinase regulatory subunit 3(PIK3R3) is overexpressed in different types of human cancer. We previously reported the important role of PIK3R3 in colorectal cancer (CRC). However, the prognosis effect of PIK3R3 in CRC is still remaining unclear. In this study, we explored online clinical databases to analyze the prognosis differences between higher and lower expression of PIK3R3 in CRC patients. Interestingly, we found that better disease-free survival (DFS) were occurred in patients with higher expression of PIK3R3, but there is no significant difference in overall survival (OS). For further, we showed that PIK3R3 could enhance 5-FU induced apoptosis by regulating the expression of thymmidine phosphorylase (TP). In conclusion, PIK3R3 could be considered as a predictor of 5-FU sensitivity for personalized treatment, and a therapeutic target for colorectal cancer.

PMID: 29370570 [PubMed - as supplied by publisher]

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Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

Related Articles

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

Cancer Biol Ther. 2018 Jan 25;:1-9

Authors: Liu J, Qu X, Shao L, Hu Y, Yu X, Lan P, Guo Q, Han Q, Zhang J, Zhang C

Abstract
Melanoma is the deadliest form of commonly encountered skin cancer, and has fast propagating and highly invasive characteristics. Pim-3, a highly expressed oncogene in melanoma, is a highly conserved serine/threonine kinase with various biological activities, such as proliferation-accelerating and anti-apoptosis effects on cancer progression. However, whether Pim-3 regulates melanoma metastasis has not been determined. Here, we constructed a Pim-3-silencing short hairpin RNA (sh-Pim-3), a TLR7-stimulating ssRNA and a dual-function vector containing a sh-Pim-3 and a ssRNA, and transfected them into the B16F10 melanoma cell line to investigate the effects of Pim-3 on migration and invasion in melanoma. We found that sh-Pim-3 inhibited B16F10 cell migration and invasion in vitro. In a tumor-bearing mouse model, sh-Pim-3 significantly downregulated pulmonary metastasis of B16F10 melanoma cell in vivo. Mechanistically, sh-Pim-3 inhibited metastasis by regulating the expression of genes related to epithelial-mesenchymal transition (EMT). Further study revealed that by promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), Pim-3 induced the expression of Slug, Snail, and ZEB1, which enhanced EMT-related changes and induced melanoma migration and invasion. Our study suggests that Pim-3 is a potential effective target for melanoma therapy.

PMID: 29370558 [PubMed - as supplied by publisher]

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Being Mindful of Mindfulness Interventions in Cancer: a systematic review of intervention reporting and study methodology

Abstract

While mindfulness–based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) have demonstrated efficacy in clinical populations, the potential therapeutic benefit of mindfulness in the context of cancer is less clear. The aim of this review was to critically appraise mindfulness intervention reporting and study methodology.

Methods

Studies using randomized control trial design and/or a control arm were included. PubMed, Medline, PsycINFO, CINAHL and Embase databases between January 1999 and April 2017 were searched. Studies were assessed on (1) reported theoretical framework, (2) intervention description, and (3) justification of modifications to standardised MBSR/MBCT. The overall quality of study design and research methodology were also assessed.

Results

Of 30 studies identified, none adhered to MBSR. Modified versions of MBSR were reported in 19 studies. Five studies reported variants of MBCT, one used a combination of MBSR/MBCT, and five inadequately documented the intervention/ theoretical framework. Overall, component and timeline modifications were poorly documented and justified. Mean intervention contact time was less than standardized MBSR/MBCT protocols. Target outcomes were poorly justified and 12 studies failed to identify a primary aim, reporting multiple outcomes. Only nine of 15 studies recruiting clinical populations included clinical cutoffs and an active therapeutic control was included in four studies.

Conclusions

Mindfulness is increasingly considered a standard therapy in psycho-oncology. While many studies proclaim benefits, there is considerable variability, modification to standardized protocols, and claims of benefit often reflect decreases in sub-clinical supportive care symptomology rather than therapeutic relief of clinically significant psychological disorders.

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Being Mindful of Mindfulness Interventions in Cancer: a systematic review of intervention reporting and study methodology

Abstract

While mindfulness–based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) have demonstrated efficacy in clinical populations, the potential therapeutic benefit of mindfulness in the context of cancer is less clear. The aim of this review was to critically appraise mindfulness intervention reporting and study methodology.

Methods

Studies using randomized control trial design and/or a control arm were included. PubMed, Medline, PsycINFO, CINAHL and Embase databases between January 1999 and April 2017 were searched. Studies were assessed on (1) reported theoretical framework, (2) intervention description, and (3) justification of modifications to standardised MBSR/MBCT. The overall quality of study design and research methodology were also assessed.

Results

Of 30 studies identified, none adhered to MBSR. Modified versions of MBSR were reported in 19 studies. Five studies reported variants of MBCT, one used a combination of MBSR/MBCT, and five inadequately documented the intervention/ theoretical framework. Overall, component and timeline modifications were poorly documented and justified. Mean intervention contact time was less than standardized MBSR/MBCT protocols. Target outcomes were poorly justified and 12 studies failed to identify a primary aim, reporting multiple outcomes. Only nine of 15 studies recruiting clinical populations included clinical cutoffs and an active therapeutic control was included in four studies.

Conclusions

Mindfulness is increasingly considered a standard therapy in psycho-oncology. While many studies proclaim benefits, there is considerable variability, modification to standardized protocols, and claims of benefit often reflect decreases in sub-clinical supportive care symptomology rather than therapeutic relief of clinically significant psychological disorders.

http://ift.tt/2Fi6jbc

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway.

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway.

Cancer Biol Ther. 2018 Jan 25;:1-8

Authors: Ibrahim S, Li G, Hu F, Hou Z, Chen Q, Li G, Luo X, Hu J, Feng Y

Abstract
Phosphoinositide-3-kinase regulatory subunit 3(PIK3R3) is overexpressed in different types of human cancer. We previously reported the important role of PIK3R3 in colorectal cancer (CRC). However, the prognosis effect of PIK3R3 in CRC is still remaining unclear. In this study, we explored online clinical databases to analyze the prognosis differences between higher and lower expression of PIK3R3 in CRC patients. Interestingly, we found that better disease-free survival (DFS) were occurred in patients with higher expression of PIK3R3, but there is no significant difference in overall survival (OS). For further, we showed that PIK3R3 could enhance 5-FU induced apoptosis by regulating the expression of thymmidine phosphorylase (TP). In conclusion, PIK3R3 could be considered as a predictor of 5-FU sensitivity for personalized treatment, and a therapeutic target for colorectal cancer.

PMID: 29370570 [PubMed - as supplied by publisher]

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Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

Cancer Biol Ther. 2018 Jan 25;:1-9

Authors: Liu J, Qu X, Shao L, Hu Y, Yu X, Lan P, Guo Q, Han Q, Zhang J, Zhang C

Abstract
Melanoma is the deadliest form of commonly encountered skin cancer, and has fast propagating and highly invasive characteristics. Pim-3, a highly expressed oncogene in melanoma, is a highly conserved serine/threonine kinase with various biological activities, such as proliferation-accelerating and anti-apoptosis effects on cancer progression. However, whether Pim-3 regulates melanoma metastasis has not been determined. Here, we constructed a Pim-3-silencing short hairpin RNA (sh-Pim-3), a TLR7-stimulating ssRNA and a dual-function vector containing a sh-Pim-3 and a ssRNA, and transfected them into the B16F10 melanoma cell line to investigate the effects of Pim-3 on migration and invasion in melanoma. We found that sh-Pim-3 inhibited B16F10 cell migration and invasion in vitro. In a tumor-bearing mouse model, sh-Pim-3 significantly downregulated pulmonary metastasis of B16F10 melanoma cell in vivo. Mechanistically, sh-Pim-3 inhibited metastasis by regulating the expression of genes related to epithelial-mesenchymal transition (EMT). Further study revealed that by promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), Pim-3 induced the expression of Slug, Snail, and ZEB1, which enhanced EMT-related changes and induced melanoma migration and invasion. Our study suggests that Pim-3 is a potential effective target for melanoma therapy.

PMID: 29370558 [PubMed - as supplied by publisher]

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via IFTTT

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway.

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway.

Cancer Biol Ther. 2018 Jan 25;:1-8

Authors: Ibrahim S, Li G, Hu F, Hou Z, Chen Q, Li G, Luo X, Hu J, Feng Y

Abstract
Phosphoinositide-3-kinase regulatory subunit 3(PIK3R3) is overexpressed in different types of human cancer. We previously reported the important role of PIK3R3 in colorectal cancer (CRC). However, the prognosis effect of PIK3R3 in CRC is still remaining unclear. In this study, we explored online clinical databases to analyze the prognosis differences between higher and lower expression of PIK3R3 in CRC patients. Interestingly, we found that better disease-free survival (DFS) were occurred in patients with higher expression of PIK3R3, but there is no significant difference in overall survival (OS). For further, we showed that PIK3R3 could enhance 5-FU induced apoptosis by regulating the expression of thymmidine phosphorylase (TP). In conclusion, PIK3R3 could be considered as a predictor of 5-FU sensitivity for personalized treatment, and a therapeutic target for colorectal cancer.

PMID: 29370570 [PubMed - as supplied by publisher]

http://ift.tt/2FiB1AX

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

Cancer Biol Ther. 2018 Jan 25;:1-9

Authors: Liu J, Qu X, Shao L, Hu Y, Yu X, Lan P, Guo Q, Han Q, Zhang J, Zhang C

Abstract
Melanoma is the deadliest form of commonly encountered skin cancer, and has fast propagating and highly invasive characteristics. Pim-3, a highly expressed oncogene in melanoma, is a highly conserved serine/threonine kinase with various biological activities, such as proliferation-accelerating and anti-apoptosis effects on cancer progression. However, whether Pim-3 regulates melanoma metastasis has not been determined. Here, we constructed a Pim-3-silencing short hairpin RNA (sh-Pim-3), a TLR7-stimulating ssRNA and a dual-function vector containing a sh-Pim-3 and a ssRNA, and transfected them into the B16F10 melanoma cell line to investigate the effects of Pim-3 on migration and invasion in melanoma. We found that sh-Pim-3 inhibited B16F10 cell migration and invasion in vitro. In a tumor-bearing mouse model, sh-Pim-3 significantly downregulated pulmonary metastasis of B16F10 melanoma cell in vivo. Mechanistically, sh-Pim-3 inhibited metastasis by regulating the expression of genes related to epithelial-mesenchymal transition (EMT). Further study revealed that by promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), Pim-3 induced the expression of Slug, Snail, and ZEB1, which enhanced EMT-related changes and induced melanoma migration and invasion. Our study suggests that Pim-3 is a potential effective target for melanoma therapy.

PMID: 29370558 [PubMed - as supplied by publisher]

http://ift.tt/2DQuMYg

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation

.


http://ift.tt/2ncwrhc

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway

.


http://ift.tt/2BubAKD

EUS dating with laser ablation against the caudate lobe or left liver tumors: a win-win proposition?

.


http://ift.tt/2neu0KT

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation

.


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PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway

.


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EUS dating with laser ablation against the caudate lobe or left liver tumors: a win-win proposition?

.


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p53 expression and subcellular survivin localization improve the diagnosis and prognosis of patients with diffuse astrocytic tumors

Abstract

Purpose

Diffuse astrocytic tumors are the most frequently occurring primary central nervous system (CNS) tumors. Their histological sub-classification into diffuse astrocytoma (DA), anaplastic astrocytoma (AA) and glioblastoma (GB) is challenging and the available prognostic factors are limited to age and tumor subtype. Biomarkers that may improve the histological sub-classification and/or serve as prognostic factors are, therefore, urgently needed. The relationship between survivin and p53 in diffuse astrocytic tumor progression and survival is currently unclear. Here, we aimed to assess the relevance of these proteins in the accuracy of the histological sub-classification of these tumors and their respective treatment responses.

Methods

One hundred and thirty-three formalin-fixed paraffin-embedded diffuse astrocytic tumor samples were included. The tumor samples were histologically reviewed and subsequently assessed for p53 and survivin expression and the presence of the IDH R132H mutation by immunohistochemistry. p53 expression levels and survivin subcellular localization patterns were correlated with histological classification and clinical outcome.

Results

We found that age and histological subtype were the only features with a prognostic impact. In addition, we found that high p53 expression levels and a nuclear survivin localization correlated with the AA subtype, whereas cytoplasmic survivin localization correlated with the GB subtype. We also found that patients carrying tumors with a high cytoplasmic survivin expression, a high nuclear survivin expression or a high p53 expression, and who did not receive radiotherapy, exhibited poorer short-term and long-term overall survival rates.

Conclusions

Our data suggest that subcellular survivin localization and p53 expression may be employed as valuable tools to improve the accuracy of the histological sub-classification of diffuse astrocytic tumors. Patients whose tumors overexpress these proteins may benefit from radiotherapy, irrespective age and/or histological classification.

http://ift.tt/2DEBNMy

miR-328 mediates a metabolic shift in colon cancer cells by targeting SLC2A1/GLUT1

Abstract

Purpose

Increasing evidence shows that altered metabolism is a critical hallmark in colon cancer. There is a strong need to explore the molecular mechanisms underlying cancer metabolism. Whether the aberrant expression of microRNAs contributes to cancer metabolism is not fully understood. miR-328 is a putative potential target of SLC2A1, but the regulating mechanism between them remains unknown. We have examined whether miR-328 directly regulates SLC2A1/GLUT1 expression in colon cancer cells.

Methods

We performed in silico bioinformatic analyses to identify miR-328-mediated molecular pathways and targets. We also performed luciferase assays and western blot analyses in LOVO and SW480 colon cancer cell lines. In addition, we assessed miR-328 expression in 47 paired tumor and normal tissue specimens from resected colon cancer patients.

Results

Luciferase reporter assays showed that miR-328 directly targeted SLC2A1 3′-untranslated region (UTR), with a significant decrease in luciferase activity in both LOVO and SW480 cell lines. These results were validated by western blot. miR-328 expression was significantly downregulated in tumor tissue compared with paired normal tissue.

Conclusions

Our results show that miR-328 targets SLC2A1/GLUT1. We suggest that miR-328 may be involved in the orchestration of the Warburg effect in colon cancer cells. Furthermore, miR‐328 expression is reduced in colon cancer patients and thus inversely correlates with the classically reported upregulated SLC2A1/GLUT1 expression in tumors.

from Cancer via ola Kala on Inoreader http://ift.tt/2DCxNYT
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miR-328 mediates a metabolic shift in colon cancer cells by targeting SLC2A1/GLUT1

Abstract

Purpose

Increasing evidence shows that altered metabolism is a critical hallmark in colon cancer. There is a strong need to explore the molecular mechanisms underlying cancer metabolism. Whether the aberrant expression of microRNAs contributes to cancer metabolism is not fully understood. miR-328 is a putative potential target of SLC2A1, but the regulating mechanism between them remains unknown. We have examined whether miR-328 directly regulates SLC2A1/GLUT1 expression in colon cancer cells.

Methods

We performed in silico bioinformatic analyses to identify miR-328-mediated molecular pathways and targets. We also performed luciferase assays and western blot analyses in LOVO and SW480 colon cancer cell lines. In addition, we assessed miR-328 expression in 47 paired tumor and normal tissue specimens from resected colon cancer patients.

Results

Luciferase reporter assays showed that miR-328 directly targeted SLC2A1 3′-untranslated region (UTR), with a significant decrease in luciferase activity in both LOVO and SW480 cell lines. These results were validated by western blot. miR-328 expression was significantly downregulated in tumor tissue compared with paired normal tissue.

Conclusions

Our results show that miR-328 targets SLC2A1/GLUT1. We suggest that miR-328 may be involved in the orchestration of the Warburg effect in colon cancer cells. Furthermore, miR‐328 expression is reduced in colon cancer patients and thus inversely correlates with the classically reported upregulated SLC2A1/GLUT1 expression in tumors.

http://ift.tt/2DCxNYT

miR-328 mediates a metabolic shift in colon cancer cells by targeting SLC2A1/GLUT1

Abstract

Purpose

Increasing evidence shows that altered metabolism is a critical hallmark in colon cancer. There is a strong need to explore the molecular mechanisms underlying cancer metabolism. Whether the aberrant expression of microRNAs contributes to cancer metabolism is not fully understood. miR-328 is a putative potential target of SLC2A1, but the regulating mechanism between them remains unknown. We have examined whether miR-328 directly regulates SLC2A1/GLUT1 expression in colon cancer cells.

Methods

We performed in silico bioinformatic analyses to identify miR-328-mediated molecular pathways and targets. We also performed luciferase assays and western blot analyses in LOVO and SW480 colon cancer cell lines. In addition, we assessed miR-328 expression in 47 paired tumor and normal tissue specimens from resected colon cancer patients.

Results

Luciferase reporter assays showed that miR-328 directly targeted SLC2A1 3′-untranslated region (UTR), with a significant decrease in luciferase activity in both LOVO and SW480 cell lines. These results were validated by western blot. miR-328 expression was significantly downregulated in tumor tissue compared with paired normal tissue.

Conclusions

Our results show that miR-328 targets SLC2A1/GLUT1. We suggest that miR-328 may be involved in the orchestration of the Warburg effect in colon cancer cells. Furthermore, miR‐328 expression is reduced in colon cancer patients and thus inversely correlates with the classically reported upregulated SLC2A1/GLUT1 expression in tumors.

from Cancer via ola Kala on Inoreader http://ift.tt/2DCxNYT
via IFTTT

miR-328 mediates a metabolic shift in colon cancer cells by targeting SLC2A1/GLUT1

Abstract

Purpose

Increasing evidence shows that altered metabolism is a critical hallmark in colon cancer. There is a strong need to explore the molecular mechanisms underlying cancer metabolism. Whether the aberrant expression of microRNAs contributes to cancer metabolism is not fully understood. miR-328 is a putative potential target of SLC2A1, but the regulating mechanism between them remains unknown. We have examined whether miR-328 directly regulates SLC2A1/GLUT1 expression in colon cancer cells.

Methods

We performed in silico bioinformatic analyses to identify miR-328-mediated molecular pathways and targets. We also performed luciferase assays and western blot analyses in LOVO and SW480 colon cancer cell lines. In addition, we assessed miR-328 expression in 47 paired tumor and normal tissue specimens from resected colon cancer patients.

Results

Luciferase reporter assays showed that miR-328 directly targeted SLC2A1 3′-untranslated region (UTR), with a significant decrease in luciferase activity in both LOVO and SW480 cell lines. These results were validated by western blot. miR-328 expression was significantly downregulated in tumor tissue compared with paired normal tissue.

Conclusions

Our results show that miR-328 targets SLC2A1/GLUT1. We suggest that miR-328 may be involved in the orchestration of the Warburg effect in colon cancer cells. Furthermore, miR‐328 expression is reduced in colon cancer patients and thus inversely correlates with the classically reported upregulated SLC2A1/GLUT1 expression in tumors.

http://ift.tt/2DCxNYT

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway.

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway.

Cancer Biol Ther. 2018 Jan 25;:1-8

Authors: Ibrahim S, Li G, Hu F, Hou Z, Chen Q, Li G, Luo X, Hu J, Feng Y

Abstract
Phosphoinositide-3-kinase regulatory subunit 3(PIK3R3) is overexpressed in different types of human cancer. We previously reported the important role of PIK3R3 in colorectal cancer (CRC). However, the prognosis effect of PIK3R3 in CRC is still remaining unclear. In this study, we explored online clinical databases to analyze the prognosis differences between higher and lower expression of PIK3R3 in CRC patients. Interestingly, we found that better disease-free survival (DFS) were occurred in patients with higher expression of PIK3R3, but there is no significant difference in overall survival (OS). For further, we showed that PIK3R3 could enhance 5-FU induced apoptosis by regulating the expression of thymmidine phosphorylase (TP). In conclusion, PIK3R3 could be considered as a predictor of 5-FU sensitivity for personalized treatment, and a therapeutic target for colorectal cancer.

PMID: 29370570 [PubMed - as supplied by publisher]

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via IFTTT

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

Cancer Biol Ther. 2018 Jan 25;:1-9

Authors: Liu J, Qu X, Shao L, Hu Y, Yu X, Lan P, Guo Q, Han Q, Zhang J, Zhang C

Abstract
Melanoma is the deadliest form of commonly encountered skin cancer, and has fast propagating and highly invasive characteristics. Pim-3, a highly expressed oncogene in melanoma, is a highly conserved serine/threonine kinase with various biological activities, such as proliferation-accelerating and anti-apoptosis effects on cancer progression. However, whether Pim-3 regulates melanoma metastasis has not been determined. Here, we constructed a Pim-3-silencing short hairpin RNA (sh-Pim-3), a TLR7-stimulating ssRNA and a dual-function vector containing a sh-Pim-3 and a ssRNA, and transfected them into the B16F10 melanoma cell line to investigate the effects of Pim-3 on migration and invasion in melanoma. We found that sh-Pim-3 inhibited B16F10 cell migration and invasion in vitro. In a tumor-bearing mouse model, sh-Pim-3 significantly downregulated pulmonary metastasis of B16F10 melanoma cell in vivo. Mechanistically, sh-Pim-3 inhibited metastasis by regulating the expression of genes related to epithelial-mesenchymal transition (EMT). Further study revealed that by promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), Pim-3 induced the expression of Slug, Snail, and ZEB1, which enhanced EMT-related changes and induced melanoma migration and invasion. Our study suggests that Pim-3 is a potential effective target for melanoma therapy.

PMID: 29370558 [PubMed - as supplied by publisher]

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via IFTTT

Non-coding RNAs, epigenetics, and cancer: tying it all together

Abstract

While only a small part of the human genome encodes for proteins, biological functions for the so-called junk genome are increasingly being recognized through high-throughput technologies and mechanistic experimental studies. Indeed, novel mechanisms of gene regulation are being discovered that require coordinated interaction between DNA, RNA, and proteins. Therefore, interdisciplinary efforts are still needed to decipher these complex transcriptional networks. In this review, we discuss how non-coding RNAs (ncRNAs) are epigenetically regulated in cancer and metastases and consequently how ncRNAs participate in the sculpting of the epigenetic profile of a cancer cell, thus modulating the expression of other RNA molecules. In the latter case, ncRNAs not only affect the DNA methylation status of certain genomic loci but also interact with histone-modifying complexes, changing the structure of the chromatin itself. We present several examples of epigenetic changes causing aberrant expression of ncRNAs in the context of tumor progression. Interestingly, there are also important epigenetic changes and transcriptional regulatory effects derived from their aberrant expression. As ncRNAs can also be used as biomarkers for diagnosis and prognosis or explored as potential targets, we present insights into the use of ncRNAs for targeted cancer therapy.

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Non-coding RNAs, epigenetics, and cancer: tying it all together

Abstract

While only a small part of the human genome encodes for proteins, biological functions for the so-called junk genome are increasingly being recognized through high-throughput technologies and mechanistic experimental studies. Indeed, novel mechanisms of gene regulation are being discovered that require coordinated interaction between DNA, RNA, and proteins. Therefore, interdisciplinary efforts are still needed to decipher these complex transcriptional networks. In this review, we discuss how non-coding RNAs (ncRNAs) are epigenetically regulated in cancer and metastases and consequently how ncRNAs participate in the sculpting of the epigenetic profile of a cancer cell, thus modulating the expression of other RNA molecules. In the latter case, ncRNAs not only affect the DNA methylation status of certain genomic loci but also interact with histone-modifying complexes, changing the structure of the chromatin itself. We present several examples of epigenetic changes causing aberrant expression of ncRNAs in the context of tumor progression. Interestingly, there are also important epigenetic changes and transcriptional regulatory effects derived from their aberrant expression. As ncRNAs can also be used as biomarkers for diagnosis and prognosis or explored as potential targets, we present insights into the use of ncRNAs for targeted cancer therapy.

http://ift.tt/2Fk4mLg

Extracellular Vesicles As miRNA Nano-Shuttles: Dual Role in Tumor Progression

Abstract

Tumor-derived extracellular vesicles (EVs) have a pleiotropic role in cancer, interacting with target cells of the tumor microenvironment, such as fibroblasts, immune and endothelial cells. EVs can modulate tumor progression, angiogenic switch, metastasis, and immune escape. These vesicles are nano-shuttles containing a wide spectrum of miRNAs that contribute to tumor progression. MiRNAs contained in extracellular vesicles (EV-miRNAs) are disseminated in the extracellular space and are able to influence the expression of target genes with either tumor suppressor or oncogenic functions, depending on both parental and target cells. Metastatic cancer cells can balance their oncogenic potential by expressing miRNAs with oncogenic function, whilst exporting miRNAs with tumor suppressor roles out of the cells. Importantly, treatment of cancer cells with specific natural and chemical compounds could induce the elimination of miRNAs with oncogenic function, thereby reducing their aggressiveness. In this review, we discuss the mechanisms by which EV-miRNAs, acting as miRNAs with oncogenic or tumor suppressor functions, could contribute to cancer progression.

http://ift.tt/2DIUGO4

Intraductal Papillary Neoplasm of the Bile Duct (IPNB): Case Report and Literature Review of a Challenging Disease to Diagnose

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Intraductal Papillary Neoplasm of the Bile Duct (IPNB): Case Report and Literature Review of a Challenging Disease to Diagnose

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Association of Optic Nerve Head Drusen with Best Vitelliform Macular Dystrophy: A Case Series

Purpose: To report the association of optic nerve head (ONH) drusen with Best vitelliform macular dystrophy (BVMD). Methods: Chart review. Patients: Five patients from 3 families. Results: Multimodal imaging and ophthalmic examination demonstrated findings consistent with ONH drusen, in association with BVMD, in 5 patients. Conclusion: We report the association of BVMD with ONH drusen in 5 patients. This combination has previously been reported only once. We recommend that patients with a diagnosis of BVMD undergo autofluorescence and ultrasound imaging of the optic nerve to help facilitate this diagnosis, as some ONH drusen can be buried.
Case Rep Ophthalmol 2018;9:76–86

http://ift.tt/2GjOH02