The prognostic role of hemoglobin levels in patients undergoing concurrent chemo-radiation for anal cancer

Abstract

Background

Concurrent chemo-radiation (CT-RT) is a standard therapy for squamous cell carcinoma of anal canal. Different clinical and biological factors may potentially affect outcome. We investigated the prognostic role of baseline hemoglobin (Hb) in a cohort of anal cancer patients submitted to CT-RT with 5-fluorouracil and mitomycin C.

Methods

Up to 161 patients with clinical stage T1-T4/N0-N3/M0 were treated. Response was assessed at 6 weeks and thereafter at 3, 6 and 12 months. Two different approaches were used:a)simultaneous integrated boost following RTOG 05-29 indications;b)first sequence of 45Gy/25 fractions to the pelvis followed by 9–14.4 Gy/5–8 fractions to the macroscopic disease. Primary endpoints were progression-free survival (PFS) and overall survival (OS).

Results

On multivariate analysis, pre-treatment Hb level had a significant correlation to OS (HR:0.53;95% CI:0.33–0.87; p = 0.001), but not to PFS (HR:0.78;95% CI:0.53–1.15; p = 0.12) Patients with pre-treatment Hb ≥ 12 g/dl had 5-year PFS and OS of 82.2%, compared to 29.3% and 32.8% for those below the threshold. The likelihood to achieve a complete remission increased by 5.6% for every single-unit (g/dl) increase in baseline Hb level over 11 g/dl. On multivariate analysis, response to treatment had a significant correlation to PFS (incomplete vs complete response – HR:5.43;95% CI:2.75–10.7; p < 0.0001) and OS (HR: 6.96;95% CI:2.96–16.5; p < 0.0001).

Conclusions

We showed that baseline Hb level is a strong indicator for poor response to RT-CT in anal cancer patients. A close clinical monitoring for incomplete response to treatment should be advised in patients with low pre-treatment Hb. The hypothesis that the preservation of adequate Hb level during treatment may lead to a better outcome needs prospective evaluation.

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Prognostic value of Dickkopf-1 and ß-catenin expression in advanced gastric cancer

Abstract

Background

Dickkopf-1 (DKK1) is a Wnt/ß-catenin pathway antagonist related to gastric cancer (GC) carcinogenesis. However, the prognostic role of combined DKK1 and ß-catenin expression in advanced GC (AGC) is not clear.

Methods

In total, 158 patients with AGC who underwent gastric resection were enrolled in this study. DKK1 and ß-catenin expression was evaluated in whole tumor sections by immunohistochemistry.

Results

DKK1 expression was high in 73 (46.2%) patients, while ß-catenin expression was positive in 51 (32.3%) patients. The expression of DKK1 was positively correlated with that of ß-catenin (P < 0.001). The combined expression of DKK1 and ß-catenin was significantly associated with high N stage (N2 and N3) (P = 0.042). In addition, patients with high DKK expression demonstrated poorer overall (OS) (P < 0.001) and disease-free survival (DFS) (P = 0.001). However, there were no differences between high DKK1 expression with ß-catenin positivity and high DKK1 expression with ß-catenin negativity (OS, P = 0.379: DFS, P = 0.255). Multivariate analysis revealed that high DKK1 alone or high DKK1 with ß-catenin positivity were independent prognostic factors for both OS (high DKK1: hazard ratio [HR], 2.130; 95% confidence interval [CI]; 1.370–3.312, P = 0.001; high DKK1 with ß-catenin positivity: HR, 2.140; 95% CI, 1.343–3.409: P = 0.001) and DFS (high DKK1: HR, 2.092; 95% CI, 1.180–3.708; P = 0.012; high DKK1 with ß-catenin positivity: HR, 2.357; 95% CI, 1.291–4.306; P = 0.005).

Conclusion

Our results indicate that high DKK1 expression regardless of ß-catenin positivity is a crucial prognostic factor for predicting tumor recurrence and survival in patients with resected AGC.

https://ift.tt/2jndzKa

Upregulation of bone morphogenetic protein 1 is associated with poor prognosis of late-stage gastric Cancer patients

Abstract

Background

Gastric cancer is the eighth most common cancer in Taiwan, with a 40% 5-year survival rate. Approximately 40% of patients are refractory to chemotherapy. Currently, the anti-HER2 therapy is the only clinically employed targeted therapy. However, only 7% patients in Taiwan are HER2-positive. Identifying candidate target genes will facilitate the development of adjuvant targeted therapy to increase the efficacy of gastric cancer treatment.

Methods

Clinical specimens were analyzed by targeted RNA sequencing to assess the expression levels of target genes. Statistical significance of differential expression and correlation between specimens was evaluated. The correlation with patient survival was analyzed as well. In vitro cell mobility was determined using wound-healing and transwell mobility assays.

Results

Expression of BMP1, COL1A1, STAT3, SOX2, FOXA2, and GATA6 was progressively dysregulated through the stages of gastric oncogenesis. The expression profile of these six genes forms an ubiquitously biomarker signature that is sufficient to differentiate cancer from non-cancerous specimens. High expression status of BMP1 correlates with poor long-term survival of late-stage patients. In vitro, suppression of BMP1 inhibits the mobility of the gastric cancer cell lines, indicating a role of BMP1 in metastasis.

Conclusions

BMP1 is upregulated in gastric cancer and is correlated with poor patient survival. Suppression of BMP1 reduced gastric cancer mobility in vitro. Our finding suggests that anti-BMP1 therapy will likely augment the efficacy of standard chemotherapy and improve the treatment outcome.

https://ift.tt/2FziAHW

LncRNA MT1JP functions as a ceRNA in regulating FBXW7 through competitively binding to miR-92a-3p in gastric cancer

Abstract

Background

Emerging evidence has shown that dysregulation function of long non-coding RNAs (lncRNAs) implicated in gastric cancer (GC). However, the role of the differentially expressed lncRNAs in GC has not fully explained.

Methods

LncRNA expression profiles were determined by lncRNA microarray in five pairs of normal and GC tissues, further validated in another 75 paired tissues by quantitative real-time PCR (qRT-PCR). Overexpression of lncRNA MT1JP was conducted to assess the effect of MT1JP in vitro and in vivo. The biological functions were demonstrated by luciferase reporter assay, western blotting and rescue experiments.

Results

LncRNA MT1JP was significantly lower in GC tissues than adjacent normal tissues, and higher MT1JP was remarkably related to lymph node metastasis and advance stage. Besides, GC patients with higher MT1JP expression had a well survival. Functionally, overexpression of lncRNA MT1JP inhibited cell proliferation, migration, invasion and promoted cell apoptosis in vitro, and inhibited tumor growth and metastasis in vivo. Functional analysis showed that lncRNA MT1JP regulated FBXW7 expression by competitively binding to miR-92a-3p. MiR-92a-3p and down-regulated FBXW7 reversed cell phenotypes caused by lncRNA MT1JP by rescue analysis.

Conclusion

MT1JP, a down-regulated lncRNA in GC, was associated with malignant tumor phenotypes and survival of GC. MT1JP regulated the progression of GC by functioning as a competing endogenous RNA (ceRNA) to competitively bind to miR-92a-3p and regulate FBXW7 expression. Our study provided new insight into the post-transcriptional regulation mechanism of lncRNA MT1JP, and suggested that MT1JP may act as a potential therapeutic target and prognosis biomarker for GC.

https://ift.tt/2I2uVtA

Linear Cutaneous Erythema in a Patient With Amyotrophic Lateral Sclerosis

(See pages 1637–8 for the Answer to the Photo Quiz.)

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In the Literature

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News

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Linear Cutaneous Erythema in a Patient With Amyotrophic Lateral Sclerosis

larva currensstrongyloidiasisStrongyloidescorticosteroidBaërmann

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Cover

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Epidemiologic and economic burden of HPV diseases in Spain: implication of additional 5 types from the 9-valent vaccine

Abstract

Background

A new nonavalent human papillomavirus (HPV) vaccine that includes genotypes 6/11/16/18/31/33/45/52/58 has been recently approved in Spain. A previous study has shown that attributable fraction of HPV related diseases in Spain is consistent with that reported in European and global studies. The aim of the present study was to estimate the annual direct costs associated to the following HPV-related diseases: genital warts, high grade precancerous lesions and cancer of cervix, vulva, vagina, anus and penis and head and neck cancer, caused by genotypes included in the nonavalent (9vHPV) and quadrivalent vaccines (4vHPV), in Spanish men and women.

Methods

Cancer registries and epidemiological studies were used to estimate the number of new annual cases of genital warts, anogenital precancerous lesions and cancer of cervix, vulva, vagina, anus, penis and head and neck, as well as the fraction attributable to HPV infection and to genotypes targeted by both vaccines in Spain. Costs per patient for each disease were obtained from the literature. In addition, 142 specialists were surveyed to estimate cost per patient of vulvar, vaginal, anal and penile precancerous lesions. The annual burden of diseases attributable to types targeted by both vaccines was estimated and compared. All results were validated by a panel of experts.

Results

In 2016, new genital warts, precancerous lesions and cancers attributable to types targeted by the 9vHPV were estimated at 49,251, 29,405 and 3381, respectively. Among them, 12,597 new precancerous lesions and 530 new cancers were related to the 5 additional types covered by the 9vHPV. Annual cost of new cases of these diseases associated to types targeted by the 4vHPV and 9vHPV were estimated at 116.7 and 150.9 million € for the Spanish National Health Service (NHS), respectively (2017 €).

Conclusions

HPV-related diseases represent a major burden for the Spanish NHS. Annual new cases and costs related to the 5 additional types from the 9vHPV represent a significant burden compared with that associated to types included in the 4vHPV.

https://ift.tt/2jkfoHD

Aspartic acid racemization of root dentin used for dental age estimation in a Polish population sample

Abstract

Precise age determination of unidentified bodies and human remains is one of the essential tasks of forensic science. The aim of this study was to assess the applicability of using the enantiomeric composition of aspartic acid racemization in root and crown dentin for dental age estimation using a Polish population sample. Coronal and root dentin from four teeth groups from the mandible were studied using gas chromatography with mass spectrometry. The results demonstrated a very high correlation between the chronological age and enantiomeric composition in both of the dentin samples. Individual linear equations of root dentin with correlation coefficients between 0.96 and 0.98 and a standard estimation error of ±2.95–4.84 years validated the application of aspartic acid racemization as a significant practical contribution to everyday forensic medical practice. Discrepancies in methodological aspects and modifications that simplify the protocol are presented.

https://ift.tt/2riFZsm

Pediatric Neuromyelitis Optica Spectrum Disorders

Abstract

Purpose of review

Neuromyelitis optica spectrum disorders (NMOSDs) are a group of inflammatory and demyelinating disorders of the central nervous system that can occur in children and adults. The classic presentation of NMOSD is characterized by optic neuritis and transverse myelitis, but other presentations are also recognized, expanding the disease as NMO spectrum disorders. The purpose of this review is to discuss the clinical features, along with management and treatment options, including potential future therapeutic options, in pediatric NMOSD.

Recent findings

The aquaporin-4 antibody (AQP4 ab) is specific for NMOSD; however, recently another antibody, the myelin oligodendrocyte glycoprotein (MOG ab) has been found in a subset of AQP4 ab-negative patients including in children. Most treatment studies are reported in adults, but retrospective studies on efficacy and safety of mycophenolate mofetil, azathioprine, and rituximab in pediatric NMOSD are available.

Summary

While some pediatric NMOSD-specific treatment studies are available, more research is needed in the mechanisms of early onset and specific treatment options in children, including whether different treatment considerations are needed for AQP4 ab as opposed to MOG ab-positive disease.

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JNK1/2 and EKR1/2 provides vital clues about tumor recurrence and survival in hepatocellular carcinoma patients

Future Oncology, Ahead of Print.


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Overexpression of p21-activated kinase 2 is correlated with high-grade oral squamous cell carcinomas

Future Oncology, Ahead of Print.


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Sentinel lymph node biopsy management after neoadjuvant treatment for breast cancer care

Future Oncology, Ahead of Print.


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Factors associated with receipt of hematopoietic cell transplantation for acute lymphoblastic leukemia

Future Oncology, Ahead of Print.


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Noninvasive detection of PD-L1 on circulating tumor cells in patient blood samples

Future Oncology, Ahead of Print.


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Chromogranin A as a biomarker for prostate cancer: is it actually relevant for clinical practice?

Future Oncology, Ahead of Print.


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Hypoxia and tumor angiogenesis in the era of hepatocellular carcinoma transarterial loco-regional treatments

Future Oncology, Ahead of Print.


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Impact of paranasal sinus invasion on advanced nasopharyngeal carcinoma treated with intensity‐modulated radiation therapy: the validity of advanced T stage of AJCC/UICC eighth edition staging system

Cancer Medicine, EarlyView.


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Preexisting radiological interstitial lung abnormalities are a risk factor for severe radiation pneumonitis in patients with small-cell lung cancer after thoracic radiation therapy

Abstract

Background

Previous studies reported that patients with preexisting radiological interstitial lung abnormalities (ILAs) were more susceptible to developing radiation pneumonitis (RP) after thoracic radiation therapy (TRT). The present study aimed to evaluate the incidence and predictors of RP after TRT in patients with small-cell lung cancer (SCLC) with or without preexisting radiological ILAs.

Methods

A total of 95 consecutive patients with SCLC between January 2015 and December 2015, who were treated with thoracic intensity-modulated radiation therapy at Shanghai Pulmonary Hospital,Tongji University School of Medicine, were analyzed. The diagnosis of ILAs was reviewed by two experienced thoracic radiologists based on the pretreatment high-resolution computed tomography imaging, such as honeycombing, subpleural reticular opacities, ground-glass opacity, and traction bronchiectasis. Univariate and multivariate analyses were used to assess the correlation of clinical factors, preexisting radiological ILAs, and dose-volume histogram-based dosimetric parameters with RP.

Results

Fifteen (15.8%) patients had preexisting radiological ILAs. The incidence of ≥ grade 2 and 3 RP at 1 year was 27.1% and 12.7% in the entire cohort, respectively. Preexisting radiological ILAs were associated with an increased risk of ≥grade 2 RP (50.0% in ILAs + vs 23.3% in ILAs−, P = 0.017) and ≥ grade 3 RP (35.8% in ILAs + vs 8.9% in ILAs−, P = 0.005) at 1 year. Preexisting radiological ILAs and smoking history (≥40 pack-years of smoking) were significant predictors of ≥grade 3 RP in multivariate analysis (P = 0.023 and 0.012, respectively).

Conclusions

Preexisting radiological ILAs and smoking history (≥40 pack-years of smoking) are associated with an increased risk of ≥grade 3 RP after TRT in patients with SCLC.

https://ift.tt/2reKchf

NKX2.5 is expressed in papillary thyroid carcinomas and regulates differentiation in thyroid cells

Abstract

Background

NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Recently, several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. We therefore hypothesized that NKX2.5 could also play a role in thyroid cancer.

Methods

The validation of NKX2.5 expression was assessed by immunohistochemistry analysis in a Brazilian case series of 10 papillary thyroid carcinoma (PTC) patients. Then, the long-term prognostic value of NKX2.5 and its correlation with clinicopathologic features of 51 PTC patients was evaluated in a cohort with 10-years follow-up (1990–1999). Besides, the effect of NKX2.5 overexpression on thyroid differentiation markers and function was also investigated in a non-tumor thyroid cell line (PCCL3).

Results

NKX2.5 was shown to be expressed in most PTC samples (8/10, case series; 27/51, cohort). Patients who had tumors expressing NKX2.5 showed lower rates of persistence/recurrence (p = 0.013). Overexpression of NKX2.5 in PCCL3 cells led to: 1) downregulation of thyroid differentiation markers (thyrotropin receptor, thyroperoxidase and sodium-iodide symporter); 2) reduced iodide uptake; 3) increased extracellular H₂O₂ generation, dual oxidase 1 mRNA levels and activity of DuOx1 promoter.

Conclusions

In summary, NKX2.5 is expressed in most PTC samples analyzed and its presence correlates to better prognosis of PTC. In vitro, NKX2.5 overexpression reduces the expression of thyroid differentiation markers and increases ROS production. Thus, our data suggests that NKX2.5 could play a role in thyroid carcinogenesis.

https://ift.tt/2KrLbTk

Clinically significant association of elevated expression of nuclear factor E2-related factor 2 expression with higher glucose uptake and progression of upper urinary tract cancer

Abstract

Background

There is growing evidence that the transcription factor nuclear factor E2-related factor 2 (Nrf2) is the major participant in regulating antioxidants and pathways for detoxifying reactive oxygen species (ROS), as well as having a vital role in tumor proliferation, invasion, and chemoresistance. It was also recently reported that Nrf2 supports cell proliferation by promoting metabolic activity. Thus, Nrf2 is involved in progression of cancer. Upper urinary tract urothelial carcinoma (UTUC) is a biologically aggressive tumor with high rates of recurrence and progression, resulting in a poor prognosis. However, the role of Nrf2 in UTUC is largely unknown.

Methods

In order to study the role of Nrf2 in UTUC from the metabolic perspective, we retrospectively assessed Nrf2 expression in the surgical specimen and the preoperative maximum standard glucose uptake (SUVmax) on [¹⁸F]fluorodeoxy-glucose positron emission tomography (¹⁸F-FDG-PET) of 107 patients with UTUC who underwent radical nephroureterectomy.

Results

Increased expression of Nrf2 in the primary lesion was correlated with less differentiated histology, local invasion, and lymph node metastasis, and was also an independent indicator of shorter overall survival according to multivariate analysis. Furthermore, increased expression of Nrf2 was associated with higher preoperative SUVmax by the primary tumor on ¹⁸F-FDG-PET, while Nrf2 expression and SUVmax were also significantly correlated in the metastatic lymph nodes. Among the 18 patients with lymph node metastasis at nephroureterectomy who underwent retroperitoneal lymph node dissection and received adjuvant chemotherapy, the patients with higher Nrf2 expression in the primary tumor had worse recurrence-free survival.

Conclusions

These results suggest that constitutive activation of Nrf2 might be linked with tumor aerobic glycolysis and progression of UTUC, indicating that Nrf2 signaling in the tumor microenvironment promotes progression of UTUC.

https://ift.tt/2FyjKDG

Limb saving surgery for Ewing’s sarcoma of the distal tibia: a case report

Abstract

Background

Ewing's sarcoma is a primary malignant tumor of bone occurring mostly in childhood. Few effective reconstruction techniques are available after wide resection of Ewing's sarcoma at the distal end of the tibia. Reconstruction after wide resection is especially difficult in children, as it is necessary to consider the growth and activity of the lower limbs.

Case presentation

A 12-year-old Japanese boy had presented with right lower leg pain at age 8 years. Imaging examination showed a bone tumor accompanied by a large extra-skeletal mass in the distal part of his tibia. The tumor was histologically diagnosed as Ewing's sarcoma. The patient received chemotherapy, followed by wide resection. Reconstruction consisted of a bone transport method involving external fixation of Taylor Spatial Frame. To prevent infection after surgery, the external fixation pin was coated with iodine. One year after surgery, the patient showed poor consolidation of bone, so iliac bone transplantation was performed on the extended bones and docking site of the distal tibia. After 20 months, tibia formation was good. Three years after surgery, there was no evidence of tumor recurrence or metastases; bone fusion was good, and he was able to run.

Conclusions

The bone transport method is an effective surgical method of reconstruction after wide resection of a bone tumor at the distal end of the tibia, if a pin can be inserted into the distal bone fragment. Coating external fixation pins with iodine may prevent postoperative infection.

https://ift.tt/2KrL9Lc

Prognostic value of an automated bone scan index for men with metastatic castration-resistant prostate cancer treated with cabazitaxel

Abstract

Background

A computer-assisted diagnostic system for analyzing bone scans (BONENAVI) calculates the automated bone scan index (aBSI). Here we evaluated the aBSI as a prognostic imaging biomarker for men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel.

Methods

We retrospectively analyzed 48 patients who received cabazitaxel for mCRPC and evaluated the ability of the aBSI to predict overall survival (OS). The Cox proportional hazards model was used to investigate the associations between baseline aBSI at cabazitaxel treatment and OS with the clinical variables as follows: age, number of cycles of docetaxel, serum prostate-specific antigen, hemoglobin (Hb), lactate dehydrogenase (LDH), and alkaline phosphatase. We determined the C-index to evaluate the discriminatory ability of our models when we included or excluded the aBSI from the analyses.

Results

The median OS after cabazitaxel treatment was 10.0 months, and patients with aBSI ≤1% achieved significantly longer OS compared with patients with aBSI ≥1%. Multivariate analysis showed that age, Hb, LDH, and aBSI were independent prognostic factors of OS. Adding aBSI to the base model increased the C-index from 0.78 to 0.80.

Conclusions

The aBSI may serve as a useful imaging biomarker for predicting OS among men with mCRPC treated with cabazitaxel. Prospective studies are required to establish the value of aBSI as prognostic imaging biomarker.

https://ift.tt/2Fy9Im9

Cancer-derived exosomes from HER2-positive cancer cells carry trastuzumab-emtansine into cancer cells leading to growth inhibition and caspase activation

Abstract

Background

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that carries a cytotoxic drug (DM1) to HER2-positive cancer. The target of T-DM1 (HER2) is present also on cancer-derived exosomes. We hypothesized that exosome-bound T-DM1 may contribute to the activity of T-DM1.

Methods

Exosomes were isolated from the cell culture medium of HER2-positive SKBR-3 and EFM-192A breast cancer cells, HER2-positive SNU-216 gastric cancer cells, and HER2-negative MCF-7 breast cancer cells by serial centrifugations including two ultracentrifugations, and treated with T-DM1. T-DM1 not bound to exosomes was removed using HER2-coated magnetic beads. Exosome samples were analyzed by electron microscopy, flow cytometry and Western blotting. Binding of T-DM1-containing exosomes to cancer cells and T-DM1 internalization were investigated with confocal microscopy. Effects of T-DM1-containg exosomes on cancer cells were investigated with the AlamarBlue cell proliferation assay and the Caspase-Glo 3/7 caspase activation assay.

Results

T-DM1 binds to exosomes derived from HER2-positive cancer cells, but not to exosomes derived from HER2-negative MCF-7 cells. HER2-positive SKBR-3 cells accumulated T-DM1 after being treated with T-DM1-containg exosomes, and treatment of SKBR-3 and EFM-192A cells with T-DM1-containing exosomes resulted in growth inhibition and activation of caspases 3 and/or 7.

Conclusion

T-DM1 binds to exosomes derived from HER2-positive cancer cells, and T-DM1 may be carried to other cancer cells via exosomes leading to reduced viability of the recipient cells. The results suggest a new mechanism of action for T-DM1, mediated by exosomes derived from HER2-positive cancer.

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Laterally spreading tumour of the distal stomach: a case report

Abstract

Background

Laterally spreading tumours (LSTs) are superficial neoplasms that usually extend laterally along the intra-luminal wall of the gastrointestinal tract. Recently, the incidence of LSTs in the colorectal mucosa has greatly increased. However, LSTs in the stomach are exceedingly rare and have never been previously reported.

Case presentation

Here, we report a 69-year-old male with epigastric pain and a gastric LST 6 cm in diameter located in the distal stomach and grossly extended into the duodenal bulb. The stomach lesion was initially diagnosed as high-grade intraepithelial neoplasia, while the duodenal lesion was diagnosed as a tubulovillous adenoma. A therapeutic strategy of endoscopic submucosal dissection and distal gastrectomy was applied. The surgeries and postoperative course were uneventful, and the patient remained asymptomatic 1 year after surgery.

Conclusions

This is a clinically significant case, as it provides detailed information regarding laterally spreading early gastric cancer and emphasizes the diagnostic and therapeutic approaches for early gastric cancerous lesions.

https://ift.tt/2Fx2U8g

C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells

Abstract

Background

Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance.

Methods

MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth.

Results

MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression.

Conclusions

Our results suggested that c-Cbl can reverse tamoxifen resistance in HER2-overexpressing breast cancer cells by inhibiting the formation of the ER-c-Src-HER2 complex.

https://ift.tt/2jn4T6t

Rupture of a subungual glomus tumor of the finger

Abstract

Background

Glomus tumor is a rare benign neoplasm, which most frequently occurs in the subungual regions of digits. Tumor rupture and infection occurred in one patient with a glomus tumor have never been reported.

Case presentation

We report a 59-year-old female presented to our hospital with a five-year history of progressively sharp pain and severe tenderness in the tip of her right middle finger. The treatment was surgical excision through a lateral incision accompanied with removal of the nail. After the surgery, the patient gained a functional recovery of her previously afflicted finger.

Conclusions

To the best of our knowledge, this is the first case of finger infection caused by a ruptured subungual glomus tumor. Patients and physicians should be aware of the properties of glomus tumor so that early diagnosis and treatment of subungual glomus tumor as well as avoidance of tumor rupture and infection can be achieved.

https://ift.tt/2FzqDVg

Characteristics of patients with missing information on stage: a population-based study of patients diagnosed with colon, lung or breast cancer in England in 2013

Abstract

Background

Stage is a key predictor of cancer survival. Complete cancer staging is vital for understanding outcomes at population level and monitoring the efficacy of early diagnosis initiatives. Cancer registries usually collect details of the disease extent but staging information may be missing because a stage was never assigned to a patient or because it was not included in cancer registration records. Missing stage information introduce methodological difficulties for analysis and interpretation of results. We describe the associations between missing stage and socio-demographic and clinical characteristics of patients diagnosed with colon, lung or breast cancer in England in 2013. We assess how these associations change when completeness is high, and administrative issues are assumed to be minimal. We estimate the amount of avoidable missing stage data if high levels of completeness reached by some Clinical Commissioning Groups (CCGs), were achieved nationally.

Methods

Individual cancer records were retrieved from the National Cancer Registration and linked to the Routes to Diagnosis and Hospital Episode Statistics datasets to obtain additional clinical information. We used multivariable beta binomial regression models to estimate the strength of the association between socio-demographic and clinical characteristics of patients and missing stage and to derive the amount of avoidable missing stage.

Results

Multivariable modelling showed that old age was associated with missing stage irrespective of the cancer site and independent of comorbidity score, short-term mortality and patient characteristics. This remained true for patients in the CCGs with high completeness. Applying the results from these CCGs to the whole cohort showed that approximately 70% of missing stage information was potentially avoidable.

Conclusions

Missing stage was more frequent in older patients, including those residing in CCGs with high completeness. This disadvantage for older patients was not explained fully by the presence of comorbidity. A substantial gain in completeness could have been achieved if administrative practices were improved to the level of the highest performing areas. Reasons for missing stage information should be carefully assessed before any study, and potential distortions introduced by how missing stage is handled should be considered in order to draw the most correct inference from available statistics.

https://ift.tt/2KwMYq2

Staining of E-selectin ligands on paraffin-embedded sections of tumor tissue

Abstract

Background

The E-selectin ligands expressed by cancer cells mediate adhesion of circulating cancer cells to endothelial cells, as well as within tissue microenvironments important for tumor progression and metastasis. The identification of E-selectin ligands within cancer tissue could yield new biomarkers for patient stratification and aid in identifying novel therapeutic targets. The determinants of selectin ligands consist of sialylated tetrasaccharides, the sialyl Lewis X and A (sLe^X and sLe^A), displayed on protein or lipid scaffolds. Standardized procedures for immunohistochemistry make use of the antibodies against sLe^X and/or sLe^A. However, antibody binding does not define E-selectin binding activity.

Methods

In this study, we developed an immunohistochemical staining technique, using E-selectin-human Ig Fc chimera (E-Ig) to characterize the expression and localization of E-selectin binding sites on paraffin-embedded sections of different cancer tissue.

Results

E-Ig successfully stained cancer cells with high specificity. The E-Ig staining show high reactivity scores in colon and lung adenocarcinoma and moderate reactivity in triple negative breast cancer. Compared with reactivity of antibody against sLe^X/A, the E-Ig staining presented higher specificity to cancer tissue with better defined borders and less background.

Conclusions

The E-Ig staining technique allows the qualitative and semi-quantitative analysis of E-selectin binding activity on cancer cells. The development of accurate techniques for detection of selectin ligands may contribute to better diagnostic and better understanding of the molecular basis of tumor progression and metastasis.

https://ift.tt/2FyX7PA

NLRP3 promotes tumor growth and metastasis in human oral squamous cell carcinoma

Abstract

Background

Inflammasomes are reported to be abnormally expressed and activated in several malignancies and play important roles in tumor development. The present study was designed to investigate the expression and function of the NLR family pyrin domain containing protein 3 (NLRP3) inflammasome in oral squamous cell carcinoma (OSCC).

Methods

NLRP3 expression in OSCC cell lines and the normal human immortalized oral epithelial cells (HIOEC) was determined by real-time PCR and western blot. Immunohistochemistry was used to examine the expression of NLRP3 and IL-1β in the paraffin-embedded OSCC tissues. The proliferation of OSCC cells was detected by the 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and cell colony formation ability of the OSCC cells was also evaluated. Tumor cell migration or invasion was measured by the transwell assay and related protein markers were determined by western blot. A mouse xenograft model was established to investigate the OSCC tumor growth in vivo.

Results

Significant higher expression of NLRP3 was observed in the OSCC cells. Obvious expression of NLRP3 and IL-1β was found in the paraffin-embedded OSCC tissues, and the NLRP3 expression levels were correlated with the tumor size, lymphonode metastatic status and IL-1β expression. Downregulating NLRP3 expression markedly reduced the cleavage of caspase-1 and production of IL-1β in OSCC cells. NLRP3 knockdown also inhibited the proliferation, migration and invasion of OSCC cells. Further investigation indicated that expressions of E-cadherin and vimentin in OSCC cells were increased, while N-cadherin expression was decreased after NLRP3 knockdown. Downregulating NLRP3 expression in OSCC cells significantly reduced the tumor growth in vivo.

Conclusions

Our data suggested that the increased expression of NLRP3 in OSCC was associated with tumor growth and metastasis. NLRP3 may be considered as a potential target for OSCC therapy.

https://ift.tt/2KvJiFg

Smokers’ interest in a lung cancer screening programme: a national survey in England

Abstract

Background

Following the recommendation of lung cancer screening in the US, screening committees in several European countries are reviewing the evidence for implementing national programmes. However, inadequate participation from high-risk groups poses a potential barrier to its effectiveness. The present study examined interest in a national lung cancer screening programme and modifiable attitudinal factors that may affect participation by smokers.

Methods

A population-based survey of English adults (n = 1464; aged 50–70 years) investigated screening intentions in different invitation scenarios, beliefs about lung cancer, early detection and treatment, worry about lung cancer risk, and stigma. Data on smoking status and perceived chances of quitting were also collected, but eligibility for lung screening in the event of a national programme was unknown.

Results

Intentions to be screened were high in all three invitation scenarios for both current (≥ 89%) and former (≥ 94%) smokers. However, smokers were less likely to agree that early-stage survival is good (43% vs. 53%; OR: 0.64, 0.46–0.88) or be willing to have surgery for an early stage, screen-detected cancer (84% vs. 94%; OR: 0.38, 0.21–0.68), compared with former smokers. Willingness to have surgery was positively associated with screening intentions; with absolute differences of 25% and 29%. Worry about lung cancer risk was also most common among smokers (48%), and one fifth of respondents thought screening smokers was a waste of NHS money.

Conclusions

A national lung cancer screening programme would be well-received in principle. To improve smokers' participation, care should be taken to communicate the survival benefits of early-stage diagnosis, address concerns about surgery, and minimise anxiety and stigma related to lung cancer risk.

https://ift.tt/2FyROQh

PEST-containing nuclear protein mediates the proliferation, migration, and invasion of human neuroblastoma cells through MAPK and PI3K/AKT/mTOR signaling pathways

Abstract

Background

PEST-containing nuclear protein (PCNP), a novel nuclear protein, is involved in cell proliferation and tumorigenesis. However, the precise mechanism of action of PCNP in the process of tumor growth has not yet been fully elucidated.

Methods

ShRNA knockdown and overexpression of PCNP were performed in human neuroblastoma cells. Tumorigenic and metastatic effects of PCNP were examined by tumor growth, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo.

Results

PCNP over-expression decreased the proliferation, migration, and invasion of human neuroblastoma cells and down-regulation of PCNP showed reverse effects. PCNP over-expression increased protein expressions of cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and cleaved poly adenosine diphosphate-ribose polymerase, as well as ratios of B-cell lymphoma-2 (Bcl-2)-associated X protein/Bcl-2 and Bcl-2-associated death promoter/B-cell lymphoma-extra large in human neuroblastoma cells, however PCNP knockdown exhibited reverse trends. PCNP over-expression increased phosphorylations of extracellular signal-regulated protein kinase 1/2, p38, c-Jun N-terminal kinase, as well as decreased phosphorylations of phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), nevertheless PCNP knockdown exhibited opposite effects. Furthermore, PCNP over-expression significantly reduced the growth of human neuroblastoma xenograft tumors by down-regulating angiogenesis, whereas PCNP knockdown markedly promoted the growth of human neuroblastoma xenograft tumors through up-regulation of angiogenesis.

Conclusions

PCNP mediates the proliferation, migration, and invasion of human neuroblastoma cells through mitogen-activated protein kinase and PI3K/AKT/mTOR signaling pathways, implying that PCNP is a therapeutic target for patients with neuroblastoma.

https://ift.tt/2jjQ6t8

Generation of a PAX6 knockout glioblastoma cell line with changes in cell cycle distribution and sensitivity to oxidative stress

Abstract

Background

The transcription factor PAX6 is expressed in various cancers. In anaplastic astrocytic glioma, PAX6 expression is inversely related to tumor grade, resulting in low PAX6 expression in Glioblastoma, the highest-grade astrocytic glioma. The aim of the present study was to develop a PAX6 knock out cell line as a tool for molecular studies of the roles PAX6 have in attenuating glioblastoma tumor progression.

Methods

The CRISPR-Cas9 technique was used to knock out PAX6 in U251 N cells. Viral transduction of a doxycycline inducible EGFP-PAX6 expression vector was used to re-introduce (rescue) PAX6 expression in the PAX6 knock out cells. The knock out and rescued cells were rigorously characterized by analyzing morphology, proliferation, colony forming abilities and responses to oxidative stress and chemotherapeutic agents.

Results

The knock out cells had increased proliferation and colony forming abilities compared to wild type cells, consistent with clinical observations indicating that PAX6 functions as a tumor-suppressor. Cell cycle distribution and sensitivity to H₂O₂ induced oxidative stress were further studied, as well as the effect of different chemotherapeutic agents. For the PAX6 knock out cells, the percentage of cells in G2/M phase increased compared to PAX6 control cells, indicating that PAX6 keeps U251 N cells in the G1 phase of the cell cycle. Interestingly, PAX6 knock out cells were more resilient to H₂O₂ induced oxidative stress than wild type cells. Chemotherapy treatment is known to generate oxidative stress, hence the effect of several chemotherapeutic agents were tested. We discovered interesting differences in the sensitivity to chemotherapeutic drugs (Temozolomide, Withaferin A and Sulforaphane) between the PAX6 expressing and non-expressing cells.

Conclusions

The U251 N PAX6 knock out cell lines generated can be used as a tool to study the molecular functions and mechanisms of PAX6 as a tumor suppressor with regard to tumor progression and treatment of glioblastoma.

https://ift.tt/2FyROjf

[ 18 F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia

Abstract

Background

The potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [¹⁸F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [¹⁸F]DPA-714 PET.

The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [¹⁸F]DPA-714 PET was performed 3 and 10 days after MCAO.

Results

Rats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [¹⁸F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group.

Conclusions

The present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [¹⁸F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application.

https://ift.tt/2Kv48on

An Interview with Michel Sadelain, MD, PhD

Human Gene Therapy, Volume 29, Issue 5, Page 530-533, May 2018.


https://ift.tt/2Ku9tfj

Efficient Non-Viral T-Cell Engineering by Sleeping Beauty Minicircles Diminishing DNA Toxicity and miRNAs Silencing the Endogenous T-Cell Receptors

Human Gene Therapy, Volume 29, Issue 5, Page 569-584, May 2018.


https://ift.tt/2FyhJr6

Effective Targeting of Multiple B-Cell Maturation Antigen–Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells

Human Gene Therapy, Volume 29, Issue 5, Page 585-601, May 2018.


https://ift.tt/2KvSTf9

miR-221 stimulates breast cancer cells and cancer-associated fibroblasts (CAFs) through selective interference with the A20/c-Rel/CTGF signaling

Abstract

Background

MicroRNA (miRNAs) are non-coding small RNA molecules that regulate gene expression by inhibiting the translation of target mRNAs. Among several dysregulated miRNAs in human cancer, the up-regulation of miR-221 has been associated with development of a variety of hematologic and solid malignancies. In this study, we investigated the involvement of miR-221 in breast cancer.

Methods

TaqMan microRNA assay was used to detect the miR-221 levels in normal cells and in MDA-MB 231 and SkBr3 breast cancer cells as well as in main players of the tumor microenvironment, namely cancer-associated fibroblasts (CAFs). miR-221 mimic sequence and locked nucleic acid (LNA)-i-miR-221 construct were used to induce or inhibit, respectively, the miR-221 expression in cells used. Quantitative PCR and western blotting analysis were performed to evaluate the levels of the miR-221 target gene A20 (TNFAIP3), as well as the member of the NF-kB complex namely c-Rel and the connective tissue growth factor (CTGF). Chromatin immunoprecipitation (ChIP) assay was performed to ascertain the recruitment of c-Rel to the CTFG promoter. Finally, the cell growth and migration in the presence of LNA-i-miR-221 or silencing c-Rel and CTGF by specific short hairpin were assessed by cell count, colony formation and boyden chambers assays. Statistical analysis was performed by ANOVA.

Results

We first demonstrated that LNA-i-miR-221 inhibits both endogenous and ectopic expression of miR-221 in our experimental models. Next, we found that the A20 down-regulation, as well as the up-regulation of c-Rel induced by miR-221 were no longer evident using LNA-i-miR-221. Moreover, we established that the miR-221 dependent recruitment of c-Rel to the NF-kB binding site located within the CTGF promoter region is prevented by using LNA-i-miR-221. Furthermore, we determined that the up-regulation of CTGF mRNA and protein levels by miR-221 is no longer evident using LNA-i-miR221 and silencing c-Rel. Finally, we assessed that cell growth and migration induced by miR-221 in MDA-MB 231 and SkBr3 breast cancer cells as well as in CAFs are abolished by LNAi-miR-221 and silencing c-Rel or CTGF.

Conclusions

Overall, these data provide novel insights into the stimulatory action of miR-221 in breast cancer cells and CAFs, suggesting that its inhibition may be considered toward targeted therapeutic approaches in breast cancer patients.

https://ift.tt/2JMgzuP

A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma

Abstract

Background

Gastric cancer is the leading cause of cancer related death worldwide. Radiation alone or combined with chemotherapy plays important role in locally advanced and metastatic gastric adenocarcinoma. MDM2–p53 interaction and downstream signaling affect cellular response to DNA damage which leads to cell cycle arrest and apoptosis. Therefore, restoring p53 function by inhibiting its interaction with MDM2 is a promising therapeutic strategy for cancer. APG-115 is a novel small molecule inhibitor which blocks the interaction of MDM2 and p53. In this study, we investigated that the radiosensitivity of APG-115 in gastric adenocarcinoma in vitro and in vivo.

Methods

The role of APG-115 in six gastric cancer cells viability in vitro was determined by CCK-8 assay. The expression level of MDM2, p21, PUMA and BAX in AGS and MKN45 cell lines was measured via real-time PCR (RT-PCR). The function of treatment groups on cell cycle and cell apoptosis were detected through Flow Cytometry assay. Clonogenic assays were used to measure the radiosensitivity of APG-115 in p53 wild type gastric cancer cell lines. Western blot was conducted to detect the protein expressions of mdm2-p53 signal pathway. Xenograft models in nude mice were established to explore the radiosensitivity role of APG-115 in gastric cancer cells in vivo.

Results

We found that radiosensitization by APG-115 occurred in p53 wild-type gastric cancer cells. Increasing apoptosis and cell cycle arrest was observed after administration of APG-115 and radiation. Radiosensitivity of APG-115 was mainly dependent on MDM2-p53 signal pathway. In vivo, APG-115 combined with radiation decreased xenograft tumor growth much more significantly than either single treatment. Moreover, the number of proliferating cells (Ki-67) significantly decreased in combination group compared with single treatment group.

Conclusions

In summary, we found that combination of MDM2-p53 inhibitor (APG-115) and radiotherapy can enhance antitumor effect both in vitro and in vivo. This is the first report on radiosensitivity of APG-115 which shed light on clinical trial of the combination therapy of radiation with APG-115 in gastric adenocarcinoma.

https://ift.tt/2I6uvSY

NHERF1 and tumor microenvironment: a new scene in invasive breast carcinoma

Abstract

Background

Tumor microenvironment (TME) includes many factors such as tumor associated inflammatory cells, vessels, and lymphocytes, as well as different signaling molecules and extracellular matrix components. These aspects can be de-regulated and consequently lead to a worsening of cancer progression. In recent years an association between the scaffolding protein Na⁺/H⁺ exchanger regulatory factor 1 (NHERF1) and tumor microenvironment changes in breast cancer (BC) has been reported.

Methods

Subcellular NHERF1 localization, vascular endothelial growth factor (VEGF), its receptor VEGFR1, hypoxia inducible factor 1 alpha (HIF-1α), TWIST1 expression and microvessel density (MVD) in 183 invasive BCs were evaluated, using immunohistochemistry on tissue microarrays (TMA). Immunofluorescence was employed to explore protein interactions.

Results

Cytoplasmic NHERF1(cNHERF1) expression was directly related to cytoplasmic VEGF and VEGFR1 expression (p = 0.001 and p = 0.027 respectively), and inversely to nuclear HIF-1α (p = 0.021) and TWIST1 (p = 0.001). Further, immunofluorescence revealed an involvement of tumor cells with NHERF1 positive staining in neo-vascular formation, suggesting a "mosaic" structure development of these neo-vessels. Survival analyses showed that loss of nuclear TWIST1 (nTWIST1) expression was related to a decrease of disease free survival (DFS) (p < 0.001), while nTWIST1-/mNHERF1+ presented an increased DFS with respect to nTWIST1+/mNHERF1- phenotype (p < 0.001). Subsequently, the analyses of nTWIST1+/cNHERF1+ phenotype selected a subgroup of patients with a worse DFS compared to nTWIST1-/cNHERF1- patients (p = 0.004).

Conclusion

Resulting data suggested a dynamic relation between NHERF1 and TME markers, and confirmed both the oncosuppressor role of membranous NHERF1 expression and the oncogene activity of cytoplasmic NHERF1.

https://ift.tt/2JIf7ta

Serum miR-22 as potential non-invasive predictor of poor clinical outcome in newly diagnosed, uniformly treated patients with diffuse large B-cell lymphoma: an explorative pilot study

Abstract

Background

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of tumors, with aggressive clinical course that renders prognostication and choice of treatment strategy difficult. Chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is the current first-line treatment.

MicroRNAs (miRNAs) are under investigation as novel diagnostic and prognostic biomarkers in several malignancies, including malignant lymphomas. While tissue miRNAs in DLBCL patients have been extensively studied as biomarkers, only few reports to date have evaluated the role of circulating/serum miRNAs as potential prognostic factors.

Here circulating/serum miRNAs, including miR-22, were investigated as potential non-invasive biomarkers, with the aim of a better prognostic stratification of DLBCL patients.

Methods

MiRNAs were selected by global expression profile of serum miRNAs of DLBCL patients, The Cancer Genome Atlas (TCGA) analysis and literature research.

Serum and tissues miRNA expression profile in de novo DLBCL patients, consecutively enrolled for this study, were detected by quantitative real-time polymerase chain reaction. Relative expression was calculated using the comparative Ct method. Statistical significance was determined using the Mann-Whitney rank sum and Fisher's exact test. Survival analysis was conducted through the use of Kaplan-Meier method. Spearman's Rho was applied to study the correlation between miRNA distributions and days to first relapse.

Experimentally validated miRNA-target interactions were assessed by miRTarBase database. Negative miRNA-mRNA correlation was evaluated in TCGA DLBCL dataset. Pathway analysis was performed by the functional annotation clustering DAVID tool.

Results

We showed a significant modulation of serum miR-22 after R-CHOP treatment compared with basal values but no difference between baseline serum miRNAs values of DLBCL patients and healthy controls. High expression level of serum miR-22 in DLBCL at diagnosis (n = 36) is associated with a worse PFS and is independent of the currently used clinical prognostic index. Integrative and pathways analysis of miR-22 identified target genes involved in different important pathways such as p53 signaling.

Conclusions

Our data suggest that miR-22 is of potential interest as non-invasive biomarker to predict clinical outcome in DLBCL patients. Characterization of miR-22 pathways can pave the way to the development of targeted therapy approaches for specific subgroups of DLBCL patients.

https://ift.tt/2rdoRET

CCL4 enhances preosteoclast migration and its receptor CCR5 downregulation by RANKL promotes osteoclastogenesis

CCL4 enhances preosteoclast migration and its receptor CCR5 downregulation by RANKL promotes osteoclastogenesis

CCL4 enhances preosteoclast migration and its receptor CCR5 downregulation by RANKL promotes osteoclastogenesis, Published online: 02 May 2018; doi:10.1038/s41419-018-0562-5

CCL4 enhances preosteoclast migration and its receptor CCR5 downregulation by RANKL promotes osteoclastogenesis

https://ift.tt/2rd77sA

Low doses of LPS exacerbate the inflammatory response and trigger death on TLR3-primed human monocytes

Low doses of LPS exacerbate the inflammatory response and trigger death on TLR3-primed human monocytes

Low doses of LPS exacerbate the inflammatory response and trigger death on TLR3-primed human monocytes, Published online: 02 May 2018; doi:10.1038/s41419-018-0520-2

Low doses of LPS exacerbate the inflammatory response and trigger death on TLR3-primed human monocytes

https://ift.tt/2HIqzsc

N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis

N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis

<i>N</i>-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis, Published online: 02 May 2018; doi:10.1038/s41419-018-0544-7

N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis

https://ift.tt/2rk8uG7

Kinesin light chain-4 depletion induces apoptosis of radioresistant cancer cells by mitochondrial dysfunction via calcium ion influx

Kinesin light chain-4 depletion induces apoptosis of radioresistant cancer cells by mitochondrial dysfunction via calcium ion influx

Kinesin light chain-4 depletion induces apoptosis of radioresistant cancer cells by mitochondrial dysfunction via calcium ion influx, Published online: 02 May 2018; doi:10.1038/s41419-018-0549-2

Kinesin light chain-4 depletion induces apoptosis of radioresistant cancer cells by mitochondrial dysfunction via calcium ion influx

https://ift.tt/2KrmLt4

GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis

GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis

GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis, Published online: 02 May 2018; doi:10.1038/s41419-018-0570-5

GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis

https://ift.tt/2rfni8P

G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas

G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas

G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas, Published online: 02 May 2018; doi:10.1038/s41419-018-0504-2

G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas

https://ift.tt/2KuZaYL

Potential role of CBX7 in regulating pluripotency of adult human pluripotent-like olfactory stem cells in stroke model

Potential role of CBX7 in regulating pluripotency of adult human pluripotent-like olfactory stem cells in stroke model

Potential role of CBX7 in regulating pluripotency of adult human pluripotent-like olfactory stem cells in stroke model, Published online: 02 May 2018; doi:10.1038/s41419-018-0519-8

Potential role of CBX7 in regulating pluripotency of adult human pluripotent-like olfactory stem cells in stroke model

https://ift.tt/2rebcgg

Hydrogen sulfide ameliorates aging-associated changes in the kidney

Abstract

Aging is associated with replacement of normal kidney parenchyma by fibrosis. Because hydrogen sulfide (H₂S) ameliorates kidney fibrosis in disease models, we examined its status in the aging kidney. In the first study, we examined kidney cortical H₂S metabolism and signaling pathways related to synthesis of proteins including matrix proteins in young and old male C57BL/6 mice. In old mice, increase in renal cortical content of matrix protein involved in fibrosis was associated with decreased H₂S generation and AMPK activity, and activation of insulin receptor (IR)/IRS-2-Akt-mTORC1-mRNA translation signaling axis that can lead to increase in protein synthesis. In the second study, we randomized 18–19 month-old male C57BL/6 mice to receive 30 μmol/L sodium hydrosulfide (NaHS) in drinking water vs. water alone (control) for 5 months. Administration of NaHS increased plasma free sulfide levels. NaHS inhibited the increase in kidney cortical content of matrix proteins involved in fibrosis and ameliorated glomerulosclerosis. NaHS restored AMPK activity and inhibited activation of IR/IRS-2-Akt-mTORC1-mRNA translation axis. NaHS inhibited age-related increase in kidney cortical content of p21, IL-1β, and IL-6, components of the senescence-associated secretory phenotype. NaHS abolished increase in urinary albumin excretion seen in control mice and reduced serum cystatin C levels suggesting improved glomerular clearance function. We conclude that aging-induced changes in the kidney are associated with H₂S deficiency. Administration of H₂S ameliorates aging-induced kidney changes probably by inhibiting signaling pathways leading to matrix protein synthesis.

https://ift.tt/2HLzRjd

Focal dose escalation for prostate cancer using 68 Ga-HBED-CC PSMA PET/CT and MRI: a planning study based on histology reference

Abstract

Background

Focal radiation therapy has gained of interest in treatment of patients with primary prostate cancer (PCa). The question of how to define the intraprostatic boost volume is still open. Previous studies showed that multiparametric MRI (mpMRI) or PSMA PET alone could be used for boost volume definition. However, other studies proposed that the combined usage of both has the highest sensitivity in detection of intraprostatic lesions. The aim of this study was to demonstrate the feasibility and to evaluate the tumour control probability (TCP) and normal tissue complication probability (NTCP) of radiation therapy dose painting using ⁶⁸Ga-HBED-CC PSMA PET/CT, mpMRI or the combination of both in primary PCa.

Methods

Ten patients underwent PSMA PET/CT and mpMRI followed by prostatectomy. Three gross tumour volumes (GTVs) were created based on PET (GTV-PET), mpMRI (GTV-MRI) and the union of both (GTV-union). Two plans were generated for each GTV. Plan95 consisted of whole-prostate IMRT to 77 Gy in 35 fractions and a simultaneous boost to 95 Gy (Plan95^PET/Plan95^MRI/Plan95^union). Plan80 consisted of whole-prostate IMRT to 76 Gy in 38 fractions and a simultaneous boost to 80 Gy (Plan80^PET/Plan80^MRI/Plan80^union). TCPs were calculated for GTV-histo (TCP-histo), which was delineated based on PCa distribution in co-registered histology slices. NTCPs were assessed for bladder and rectum.

Results

Dose constraints of published protocols were reached in every treatment plan. Mean TCP-histo were 99.7% (range: 97%–100%) and 75.5% (range: 33%–95%) for Plan95^union and Plan80^union, respectively. Plan95^union had significantly higher TCP-histo values than Plan95^MRI (p = 0.008) and Plan95^PET (p = 0.008). Plan80^union had significantly higher TCP-histo values than Plan80^MRI (p = 0.012), but not than Plan80^PET (p = 0.472).

Plan95^MRI had significantly lower NTCP-rectum than Plan95^union (p = 0.012). No significant differences in NTCP-rectum and NTCP-bladder were observed for all other plans (p > 0.05).

Conclusions

IMRT dose escalation on GTVs based on mpMRI, PSMA PET/CT and the combination of both was feasible. Boosting GTV-union resulted in significantly higher TCP-histo with no or minimal increase of NTCPs compared to the other plans.

https://ift.tt/2HJx7qN

Assessment of the quality of patient-oriented information over internet on testicular cancer

Abstract

Background

This study aimed to assess the quality and readability of patient education information available on the internet on testicular cancer.

Methods

Internet searches were performed using the keywords 'testicular cancer', 'testicular tumour', 'testicular tumor', 'testicular malignancy', 'germ cell tumour' and 'germ cell tumor' using Google, Yahoo! And Bing search engines with default settings. The first 50 web links appeared in each search engine were evaluated for their readability by using the validated Flesch Reading Ease Score (FRES) while accessibility, usability and reliability were assessed using the LIDA tool. The quality was assessed using DISCERN instrument. Non-parametric tests were used for statistical analysis.

Results

Overall, 900 websites were assessed and 62 websites were included in the analysis. Twenty two (22) websites (35.5%) were certified by Health on the Net Foundation code of conduct (HON code). The majority (n = 57, 91.9%) were non-governmental websites. The median FRES score was 51.6 (range: 28.1–74.1), the overall median LIDA score was 115 (range: 81–147); accessibility 55 (range: 46–61), reliability 22 (range: 8–45) and usability 38.5 (range: 21–50), while the median DISCERN score was 43.5 (range: 16–69). The DISCERN score was significantly associated with the overall LIDA score and usability and reliability components of the LIDA score (p < 0.001). However, no significant associations were observed between readability and accessibility. A significant correlation was noted between usability and reliability components of the LIDA score (Spearman's rho: 0.789, p < 0.001).

Conclusion

In this study, the readability, reliability and quality scores of most websites were found to be suboptimal and hence, there is potential for improvement. As the internet is expanding rapidly as a readily available source of information to the public, it is essential to implement steps to ensure that highest quality information is provided without any commercial motivation or bias.

https://ift.tt/2reKfK6

LYL1 gene amplification predicts poor survival of patients with uterine corpus endometrial carcinoma: analysis of the Cancer genome atlas data

Abstract

Background

Somatic amplifications of the LYL1 gene are relatively common occurrences in patients who develop uterine corpus endometrial carcinoma (UCEC) as opposed to other cancers. This study was undertaken to determine whether such genetic alterations affect survival outcomes of UCEC.

Methods

In 370 patients with UCEC, we analysed clinicopathologic characteristics and corresponding genomic data from The Cancer Genome Atlas database. Patients were stratified according to LYL1 gene status, grouped as amplification or non-amplification. Heightened levels of cancer-related genes expressed in concert with LYL1 amplification were similarly investigated through differentially expressed gene and gene set enrichment analyses. Factors associated with survival outcomes were also identified.

Results

Somatic LYL1 gene amplification was observed in 22 patients (5.9%) with UCEC. Patients displaying amplification (vs. non-amplification) were significantly older at the time of diagnosis and more often were marked by non-endometrioid, high-grade, or advanced disease. In survival analysis, the amplification subset showed poorer progression-free survival (PFS) and overall survival (OS) rates (3-year PFS: 34.4% vs. 79.9%, P = 0.031; 5-year OS: 25.1% vs. 84.9%, P = 0.014). However, multivariate analyses adjusted for tumor histologic type, grade, and stage did not confirm LYL1 gene amplification as an independent prognostic factor for either PFS or OS. Nevertheless, MAPK, WNT, and cell cycle pathways were significantly enriched by LYL1 gene amplification (P < 0.001, P = 0.002, and P = 0.004, respectively).

Conclusions

Despite not being identified as an independent prognostic factor in UCEC, LYL1 gene amplification is associated with other poor prognostic factors and correlated with upregulation of cancer-related pathways.

https://ift.tt/2JK9ESR

Correction to: Secretomes reveal several novel proteins as well as TGF-β1 as the top upstream regulator of metastatic process in breast cancer

Abstract

In the original publication of the article, Acknowledgement section was missed out and Table 1 was published incompletely. The Acknowledgment and complete table 1 are given in this correction. The original article has been corrected.

https://ift.tt/2w6aVS8

Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human

Abstract

Human genetic studies are rapidly identifying variants that increase risk for neurodevelopmental disorders. However, it remains unclear how specific mutations impact brain function and contribute to neuropsychiatric risk. Chromosome 16p11.2 deletion is one of the most common copy number variations in autism and related neurodevelopmental disorders. Using resting state functional MRI data from the Simons Variation in Individuals Project (VIP) database, we show that 16p11.2 deletion carriers exhibit impaired prefrontal connectivity, resulting in weaker long-range functional coupling with temporal-parietal regions. These functional changes are associated with socio-cognitive impairments. We also document that a mouse with the same genetic deficiency exhibits similarly diminished prefrontal connectivity, together with thalamo-prefrontal miswiring and reduced long-range functional synchronization. These results reveal a mechanistic link between specific genetic risk for neurodevelopmental disorders and long-range functional coupling, and suggest that deletion in 16p11.2 may lead to impaired socio-cognitive function via dysregulation of prefrontal connectivity.

https://ift.tt/2JFrExx

Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis

Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis

Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis, Published online: 02 May 2018; doi:10.1038/s41416-018-0077-y

Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis

https://ift.tt/2r9ET2L

Improving influenza vaccines: challenges to effective implementation

Fan Zhou | Mai-Chi Trieu | Richard Davies | Rebecca Jane Cox

https://ift.tt/2rdQb6b

Endocytosis regulation by autophagy proteins in MHC restricted antigen presentation

Christian W .Keller | Monica Loi | Laure-Anne Ligeon | Monique Gannagé | Jan D Lünemann | Christian Münz

https://ift.tt/2JIYgq1

Role of calcium permeable channels in dendritic cell migration

Pablo J Sáez | Juan C Sáez | Ana-María Lennon-Duménil | Pablo Vargas

https://ift.tt/2I1Y9ZA

Knowledge of Causes of Cancer Low in General Population

TUESDAY, May 1, 2018 -- Among the general population, awareness of actual and mythical causes of cancer is poor, according to a study published online April 25 in the European Journal of Cancer. Lion Shahab, Ph.D., from University College London,...

https://ift.tt/2FyplKi

Doctors Generally Confident With Deprescribing for Elderly

TUESDAY, May 1, 2018 -- Physicians are generally comfortable with deprescribing for elderly patients, although there are several barriers to deprescribing, according to a study published online April 22 in the Journal of Clinical Pharmacy and...

https://ift.tt/2Ksxjby

Glyburide Not Noninferior to Insulin for Gestational Diabetes

TUESDAY, May 1, 2018 -- For women with gestational diabetes, glyburide is not noninferior to insulin, according to a study published in the May 1 issue of the Journal of the American Medical Association. Marie-Victoire Sénat, M.D., Ph.D., from the...

https://ift.tt/2FzYflR

Synthetic Opioid Involvement in Opioid-Related Deaths Up

TUESDAY, May 1, 2018 -- Synthetic opioid involvement in opioid-related overdose deaths increased significantly from 2010 to 2016, according to a research letter published in the May 1 issue of the Journal of the American Medical...

https://ift.tt/2jnhSFe

Practices Should Be Aware of Correct Way to Fire Employees

TUESDAY, May 1, 2018 -- Physicians should be aware of the correct protocol for, as well as the laws involved in, firing employees, according to a report published in Medical Economics. The article suggests compiling an employee handbook, which...

https://ift.tt/2FzYddJ

Protective Effect of Ganoderma Triterpenoids on Cadmium-Induced Testicular Toxicity in Chickens

Abstract

Studies have shown that cadmium can cause chicken testicular damage, but a protective effect of Ganoderma triterpenoids on cadmium-induced testicular damage in chickens has not yet been reported. The present study was designed to research the protective effect of Ganoderma triterpenoids on cadmium-induced testicular damage in chicken. Eighty healthy 7-day-old Hyline egg laying chickens were randomly divided into four groups with 20 in each group. The control group was fed with normal full-fodder, the model group was fed with normal full-fodder with 140 mg/kg of CdCl₂, the Ganoderma triterpenoid treatment group was fed with a full-fodder diet containing 140 mg/kg of CdCl₂ and 0.5 mL of Ganoderma triterpenoid solution (20 mg/mL), and the Ganoderma triterpenoid group was fed normal full-fodder and 0.5 mL of Ganoderma triterpenoid solution (20 mg/mL) gavage. The chickens were euthanized at 20, 40, and 60 days, respectively, and the testes were harvested. The changes of cadmium contents, the antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)), peroxide (malondialdehyde (MDA)), inflammatory factors (interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α)), and apoptosis-related proteins (Bax, Bcl-2, and Caspase-3) were detected. The pathological sections of the testes were made at the same time. The results suggested that Ganoderma triterpenoids could reduce the accumulation of cadmium in testis tissue; reduce the content of IL-1β, IL-6, and TNF-α in cadmium poisoning testis; significantly increase the activity of SOD and GSH-Px; decrease the content of MDA; regulate the expression of Bax, Caspase-3, and Bcl-2; and reduce the damage of testicular tissue. The results showed that Ganoderma triterpenoids have a protective effect on cadmium-induced testicular injury in chicken.

https://ift.tt/2rieX4m

Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis

https://ift.tt/2HIlAnn

Central xanthoma of the jaw in association with Noonan syndrome

Xanthomas are histiocytic lesions of the skin, soft tissue and bone and are generally considered to be reactive in nature. When they arise in the bones of the jaw, they are referred to as central xanthomas. New evidence supports the hypothesis that central xanthomas are a separate and distinct entity from their extragnathic counterparts. Noonan syndrome (NS) is an autosomal dominant disorder that has been associated with giant cell lesions which also commonly occur in the jaw. We present a case of a 15year-old-male with NS who presented with a radiolucent lesion of the mandible that on excision, was found to be a central xanthoma.

https://ift.tt/2Kts9vH

Histology of colorectal adenocarcinoma with double somatic mismatch repair mutations is indistinguishable from those caused by lynch syndrome

Lynch syndrome (LS) is the most common form of hereditary colon cancer (CRC). Germline mutations in the mismatch repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele leads to cancer development. Universal tumor screening for LS is routinely performed on CRC, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients.

https://ift.tt/2FyoNUD

Clonality analysis of multifocal ipsilateral breast carcinomas using X-chromosome inactivation patterns

The definition of multifocal breast cancer is ambiguous, and its incidence varies depending on the definition and detection methods. Multifocal breast cancers either have the same clonal origin or arise from completely distinct progenitor cells. The current American Joint Committee on Cancer Staging system and College of American Pathologists breast tumor guidelines state that only the largest tumor needs to be staged and studied immunohistochemically, on the assumption that they are of the same origin.

https://ift.tt/2KuoLRB

H3 K27 M-mutant diffuse midline gliomas in different anatomical locations

The histone H3 K27 M mutation has been frequently reported in the majority of diffuse midline gliomas. However, the relationship between the H3 K27 M mutation and clinical outcomes of gliomas from different anatomical locations is still not fully understood. A total of 120 patients with diffuse midline gliomas were selected for this retrospective observational study. The status of H3 K27 M, ATRX, TP53 and IDH was evaluated using immunohistochemistry and Sanger sequencing. Of the 120 cases aged from 4 to 76years (median=27years), 61 (50.8%) were harboring the H3 K27 M mutation.

https://ift.tt/2Fy6KOv

PSMD5 inactivation promotes 26S proteasome assembly during colorectal tumor progression

Protein degradation by the ubiquitin-proteasome system (UPS) is central to protein homeostasis and cell survival. The active 26S proteasome is a large protease complex consisting of a catalytic 20S subunit and 19S regulatory particles. Cancer cells are exposed to considerable protein overload due to high metabolic rates, reprogrammed energy metabolism and aneuploidy. Here we report a mechanism that facilitates the assembly of active 26S proteasomes in malignant cells. Upon tumorigenic transformation of the gut epithelium, 26S proteasome assembly was significantly enhanced, but levels of individual subunits were not changed. This enhanced assembly of 26S proteasomes increased further with tumor progression and was observed specifically in transformed cells, but not in other rapidly dividing cells. Moreover, expression of PSMD5, an inhibitor of proteasome assembly, was reduced in intestinal tumors and silenced with tumor progression. Re-expression of PSMD5 in tumor cells caused decreased 26S assembly and accumulation of poly-ubiquitinated proteins. These results suggest that inhibition of cancer-associated proteasome assembly may provide a novel therapeutic strategy to selectively kill cancer cells.

https://ift.tt/2HLWzI7

Acupuncture possible treatment for dental anxiety

Researchers have found evidence that acupuncture could help people who experience dental anxiety.

https://ift.tt/2HMC5il

Driving CARs Across New Borders

Human Gene Therapy, Volume 29, Issue 5, Page 529-529, May 2018.


https://ift.tt/2KqR57c

Muscle Imbalances: Testing and Training Functional Eccentric Hamstring Strength in Athletic Populations

The hamstrings are a group of muscles that are sometimes problematic for athletes, resulting in soft tissue injury in the lower limbs. To prevent such injuries, functional training of the hamstrings requires intensive eccentric contractions. Additionally, hamstring function should be tested in relation to quadricep function at different contraction speeds.

https://ift.tt/2HMCNfv

Practical Use of RNA Interference: Oral Delivery of Double-stranded RNA in Liposome Carriers for Cockroaches

This manuscript demonstrates the depletion of gene expression in the midgut of the German cockroach through oral ingestion of double-stranded RNA encapsulated in liposomes.

https://ift.tt/2rdziZ4

Clinical Upstaging of NSCLC Seen With Each Progressive Week

TUESDAY, May 1, 2018 -- For patients with non-small-cell lung cancer (NSCLC), significant upstaging can occur in each successive week from initial staging to surgery, according to a study presented at the annual meeting of the American Association...

https://ift.tt/2jpyw7j

Severe Obesity Tied to Faster Progression to Disability With RA

TUESDAY, May 1, 2018 -- Severe obesity is associated with more rapid progression of disability in patients with rheumatoid arthritis (RA), according to a study published online April 30 in Arthritis Care & Research. Joshua F. Baker, M.D., from...

https://ift.tt/2HHDtTg

Anesthesia Before Age 3 Not Linked to Intelligence Deficits

TUESDAY, May 1, 2018 -- Multiple exposures to anesthesia before the age of 3 years may have neuropsychological impacts, though intelligence does not appear to be affected, according to a study published online April 18 in Anesthesiology. David O....

https://ift.tt/2jmLpPc

Maternal, Child Sugar Intake Could Impact Child Cognition

TUESDAY, May 1, 2018 -- Greater sugar consumption during pregnancy and early childhood may adversely impact child cognition, according to a study published online April 16 in the American Journal of Preventive Medicine. Juliana F.W. Cohen, Sc.D.,...

https://ift.tt/2HIc5o1

Early Readmissions More Preventable Than Later Ones

TUESDAY, May 1, 2018 -- Early general medicine readmissions are more likely than late readmissions to be preventable with hospital-based interventions, according to a study published online May 1 in the Annals of Internal of Medicine. Kelly L....

https://ift.tt/2rcOQMM

Perioperative MACCEs More Common With Diabetes

TUESDAY, May 1, 2018 -- Perioperative major adverse cardiovascular and cerebrovascular events (MACCEs) are more common among patients with diabetes mellitus (DM), according to a study published online April 4 in Diabetes Care. Jonathan D. Newman,...

https://ift.tt/2HHCpPj

Timely Receipt of PCI in STEMI Up With Hospital Bypass Policy

TUESDAY, May 1, 2018 -- Adoption of policies allowing emergency medical services (EMS) to bypass non-percutaneous coronary intervention (PCI) capable hospitals for patients with ST-segment elevation myocardial infarction (STEMI) is associated with...

https://ift.tt/2jiBKcu

Metabolically Healthy Obesity Not Without Risk of CVD

TUESDAY, May 1, 2018 -- Metabolically healthy obesity (MHO) is not a stable or reliable indicator of future cardiovascular disease (CVD) risk, according to a study published in the May 1 issue of the Journal of the American College of...

https://ift.tt/2HNra8d

Certain Foods May Impact Timing of Menopause

TUESDAY, May 1, 2018 -- Intake of some food groups and nutrients may affect the timing of menopause, according to a study published online April 30 in the Journal of Epidemiology & Community Health. Yashvee Dunneram, from the University of Leeds...

https://ift.tt/2rb9FIG

Clinically Significant Anxiety Tied to Subsequent Dementia Risk

TUESDAY, May 1, 2018 -- Clinically significant anxiety in midlife is associated with increased subsequent dementia risk over an interval of at least 10 years, according to a review published online April 30 in BMJ Open. Amy Gimson, from the...

https://ift.tt/2HJ9pXm

April 2018 Briefing - Emergency Medicine

Here are what the editors at HealthDay consider to be the most important developments in Emergency Medicine for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes...

https://ift.tt/2jiCkHk

April 2018 Briefing - Critical Care

Here are what the editors at HealthDay consider to be the most important developments in Critical Care for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...

https://ift.tt/2HHNrUM

April 2018 Briefing - Nephrology

Here are what the editors at HealthDay consider to be the most important developments in Nephrology for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...

https://ift.tt/2rdoyKx

April 2018 Briefing - Dermatology

Here are what the editors at HealthDay consider to be the most important developments in Dermatology for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...

https://ift.tt/2HHypOU

April 2018 Briefing - Surgery

Here are what the editors at HealthDay consider to be the most important developments in Surgery for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...

https://ift.tt/2rceIbs

April 2018 Briefing - Urology

Here are what the editors at HealthDay consider to be the most important developments in Urology for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...

https://ift.tt/2HKLhUm

April 2018 Briefing - Pediatrics

Here are what the editors at HealthDay consider to be the most important developments in Pediatrics for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...

https://ift.tt/2jlWkc5

April 2018 Briefing - Gastroenterology

Here are what the editors at HealthDay consider to be the most important developments in Gastroenterology for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...

https://ift.tt/2HIc4QZ

April 2018 Briefing - Pain Management

Here are what the editors at HealthDay consider to be the most important developments in Pain Management for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...

https://ift.tt/2jori33

April 2018 Briefing - Orthopedics

Here are what the editors at HealthDay consider to be the most important developments in Orthopedics for April 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...

https://ift.tt/2rb9Dk2

Experimental Procedure for Laboratory Studies of In Situ Burning : Flammability and Burning Efficiency of Crude Oil

Here, we present a protocol to simultaneously study the flammability and burning efficiency of fresh and weathered crude oil under conditions that simulate in situ burning operations on the sea.

https://ift.tt/2HFLFHH

Construction of Synthetic Phage Displayed Fab Library with Tailored Diversity

This protocol describes a detailed procedure for the construction of a phage-displayed synthetic antibody library with tailored diversity. Synthetic antibodies have broad applications from basic research to disease diagnostics and therapeutics.

https://ift.tt/2rdgRmM

Lowbush cranberry acts through DAF-16/FOXO signaling to promote increased lifespan and axon branching in aging posterior touch receptor neurons

Abstract

Medicinal berries are appreciated for their health benefits, in traditional ecological knowledge and nutrition science. Determining the cellular mechanisms underlying the effects of berry supplementation may contribute to our understanding of aging. Here, we report that lowbush cranberry (Vaccinium vitis-idaea) treatment causes marked nuclear localization of the central aging-related transcription factor DAF-16/FOXO in aged Caenorhabditis elegans. Further, functional DAF-16 is required for the lifespan extension, improved mechanosensation, and posterior touch receptor neuron morphological changes induced by lowbush cranberry treatments. DAF-16 is not observed in nuceli nor required for lifespan extension in lifespan-extending Alaskan blueberry treatments and, while DAF-16 is not visibly induced into the nucleus in lifespan-extending Alaskan chaga treatments, it is required for chaga-induced lifespan extension. These findings underscore the importance of DAF-16 in the aging of whole organisms and touch receptor neurons and also, importantly, indicate that this critical pathway is not always activated upon consumption of functional foods that impact aging.

https://ift.tt/2I8HZO7

Enjoying the Sounds of Nashville

Reminiscing about your time in Nashville at AAA 2018? While there was much to do at the convention center, perhaps you also found a little time to explore the surrounding area? If so, you may have strolled across the John Seigenthaler Pedestrian Bridge and noticed music emanating from loudspeakers as you reached the zenith. 

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https://ift.tt/2rfrzd9

The Diffusion of Passive Tracers in Laminar Shear Flow

A protocol for the study of the diffusion of passive tracers in laminar pressure-driven flow is presented. The procedure is applicable to various capillary pipe geometries.

https://ift.tt/2KvkP2W

Tracking Infiltration Front Depth Using Time-lapse Multi-offset Gathers Collected with Array Antenna Ground Penetrating Radar

Here we present a Ground Penetrating Radar (GPR) system based on a ground-coupled, densely populated antenna array for monitoring the dynamic process of subsurface water infiltration. A time-lapse radar image of the infiltration process allowed estimating the depth of the wetting front during the course of the infiltration process.

https://ift.tt/2FwK94M

Boy saves brother with skills learned at first responder camp

Zimori Hall had just completed a one-week "911 Jr. First Responder Camp" where he learned the basics of first aid, CPR training and the Heimlich Maneuver

https://ift.tt/2HHPvAc

Ventriculoperitoneal shunts in non-HIV cryptococcal meningitis

Persistent and uncontrollable intracranial hypertension (ICH) and difficulty in reducing Cryptococcus count are severe problems in cryptococcal meningitis (CM) patients. The therapeutic effects of ventriculope...

https://ift.tt/2Fxk1qp

Severe localised granulomatosis with polyangiitis (Wegener’s granulomatosis) manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review

Granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) is a multisystem vasculitis of small- to medium-sized blood vessels. Cranial involvement can result in cranial nerve palsies and, rarel...

https://ift.tt/2KvazYu

Mitochondrial Ca2+ Retention Capacity Assay and Ca2+-triggered Mitochondrial Swelling Assay

This protocol aims to describe a method to examine the Ca2+ retention capacity and Ca2+- triggered mitochondrial swelling of isolated mitochondria of SH-SY5Y cells step-by-step.

https://ift.tt/2jiQoAx

Researchers developing drone air ambulance

Caltech researchers have designed what they call a "personal rescue system" that was created to quickly get a patient to a hospital or doctor

https://ift.tt/2HF5qPI

MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease

Purpose: Germline mutations within the MEIS-interaction domain of HOXB13 have implicated a critical function for MEIS-HOX interactions in prostate cancer etiology and progression.  The functional and predictive role of changes in MEIS expression within prostate tumor progression, however, remain largely unexplored. Experimental Design: Here we utilize RNA expression datasets, annotated tissue microarrays, and cell-based functional assays to investigate the role of MEIS1 and MEIS2 in prostate cancer and metastatic progression. Results: These analyses demonstrate a stepwise decrease in the expression of both MEIS1 and MEIS2 from benign epithelia, to primary tumor, to metastatic tissues.  Positive expression of MEIS proteins in primary tumors, however, is associated with a lower hazard of clinical metastasis (HR = 0.28) after multivariable analysis.  Pathway and gene set enrichment analyses identified MEIS-associated networks involved in cMYC signaling, cellular proliferation, motility, and local tumor environment.  Depletion of MEIS1 and MEIS2 resulted in increased tumor growth over time in vivo, and decreased MEIS expression in both patient-derived tumors and MEIS-depleted cell lines was associated with increased expression of the pro-tumorigenic genes cMYC and CD142, and decreased expression of AXIN2, FN1, ROCK1, SERPINE2, SNAI2, and TGFb2. Conclusions: These data implicate a functional role for MEIS proteins in regulating cancer progression, and support a hypothesis whereby tumor expression of MEIS1 and MEIS2 expression confers a more indolent prostate cancer phenotype, with a decreased propensity for metastatic progression. 

https://ift.tt/2HH8ZRu

Interferon Gamma Messenger RNA Signature in Tumor Biopsies Predicts Outcomes in Patients with Non-Small-Cell Lung Carcinoma or Urothelial Cancer Treated with Durvalumab

Purpose: To identify a predictive biomarker for durvalumab, an anti-programmed death ligand 1 (PD-L1) monoclonal antibody. Experimental Design: RNA sequencing of 97 advanced-stage non-small-cell lung carcinoma (NSCLC) biopsies from a nonrandomized phase 1b/2 clinical trial (1108/NCT01693562) were profiled to identify a predictive signature; 62 locally advanced or metastatic urothelial cancer (UC) tumors from the same study were profiled to confirm predictive utility of the signature. Thirty NSCLC patients provided pre- and posttreatment tumors for messenger RNA (mRNA) analysis. NSCLC with ≥25% tumor cells and UC with ≥25% tumor or immune cells stained for PD-L1 at any intensity were scored PD-L1 positive (PD-L1+). Kaplan-Meier and Cox proportional hazards analyses were used to adjust for gender, age, prior therapies, histology, ECOG, liver metastasis, and smoking. Tumor mutation burden (TMB) was calculated using data from The Cancer Genome Atlas (TCGA). Results: In the NSCLC discovery set, a four-gene interferon gamma (IFN)-positive (IFN+) signature comprising IFN, CD274, LAG3, and CXCL9 was associated with higher overall response rates, longer median progression-free survival, and overall survival compared with signature-low patients. IFN+-signature NSCLC patients had improved survival regardless of immunohistochemistry (IHC) PD-L1 status. These associations were replicated in a UC cohort. The IFN+ signature was induced twofold (P = 0.003) by durvalumab after 8 weeks of therapy in NSCLC patients, and baseline signature was associated with TMB but not survival in TCGA data. Conclusions: The IFN+ mRNA signature may assist in identifying patients with improved outcomes to durvalumab, independent of PD-L1 assessed by IHC.

https://ift.tt/2jkgmnl

IGF2/IR/IGF1R pathway in tumor cells and myofibroblasts mediates resistance to EGFR inhibition in cholangiocarcinoma

Purpose: Cholangiocarcinoma (CCA) is a desmoplastic tumor of the biliary tree in which epidermal growth factor receptor (EGFR) is overexpressed and contributes to cancer progression. Although, EGFR has been envisaged as a target for therapy, treatment with tyrosine kinase inhibitors (TKI) such as erlotinib did not provide therapeutic benefit in patients with CCA, emphasizing the need to investigate resistance mechanisms against EGFR inhibition. Experimental Design: Resistant CCA cells to EGFR inhibition were obtained upon long time exposure of cells with erlotinib. Cell signaling, viability, migration and spheroid growth were determined in vitro, and tumor growth was evaluated in CCA xenograft models. Results: Erlotinib-resistant CCA cells displayed metastasis-associated signatures that correlated with a marked change in cell plasticity associated with an epithelial-mesenchymal transition (EMT) and a cancer stem cell (CSC)-like phenotype. Resistant cells exhibited an up-regulation of insulin receptor (IR) and insulin-like growth factor (IGF) 1 receptor (IGF1R), along with an increase in IGF2 expression. IR/IGF1R inhibition reduced EMT and CSC-like traits in resistant cells. In vivo, tumors developed from resistant CCA cells were larger and exhibited a more prominent stromal compartment, enriched in cancer-associated fibroblasts (CAF). Pharmacological co-inhibition of EGFR and IR/IGF1R reduced tumor growth and stromal compartment in resistant tumors. Modeling of CCA-CAF crosstalk showed that IGF2 expressed by fibroblasts boosted IR/IGF1R signaling in resistant cells. Furthermore, IR/IGF1R signaling positively regulated fibroblast proliferation and activation. Conclusions: To escape EGFR-TKI treatment, CCA tumor cells develop an adaptive mechanism by undergoing an IR/IGF1R-dependent phenotypic switch, involving a contribution of stromal cells.

https://ift.tt/2HIHOpe

CD20-TCB with obinutuzumab pretreatment as next generation treatment of hematological malignancies

Purpose: Despite promising clinical activity, T cell engaging therapies including T cell bispecific antibodies (TCBs) are associated with severe side effects requiring the use of step-up-dosing (SUD) regimens to mitigate safety. Here, we present a next generation CD20-targeting TCB (CD20-TCB) with significantly higher potency and a novel approach enabling safer administration of such potent drug. Experimental design: We developed CD20-TCB based on the 2:1 TCB molecular format and characterized its activity pre-clinically. We also applied a single administration of obinutuzumab (Gazyva pre-treatment, Gpt) prior to the first infusion of CD20-TCB as a way to safely administer such a potent drug. Results: CD20-TCB is associated with a long half-life and high potency enabled by high-avidity bivalent binding to CD20 and head-to-tail orientation of B and T cell binding domains in a 2:1 molecular format. CD20-TCB displays considerably higher potency than other CD20-TCB antibodies in clinical development and is efficacious on tumor cells expressing low levels of CD20. CD20-TCB also displays potent activity in primary tumor samples with low effector:target ratios. In vivo, CD20-TCB regresses established tumors of aggressive lymphoma models. Gpt enables profound B cell depletion in peripheral blood and secondary lymphoid organs and reduces T cell activation and cytokine release in the peripheral blood thus increasing the safety of CD20-TCB administration. Gpt is more efficacious and safer than SUD. Conclusions: CD20-TCB and Gpt represent a potent and safer approach for treatment of lymphoma patients and are currently being evaluated in Phase I, multicenter study in patients with relapsed/refractory NHL (NCT03075696).

https://ift.tt/2I0SBhY

A multi-center Phase 1 trial of ipilimumab in myelodysplastic syndrome patients following hypomethylating agent failure

Purpose: After failure of hypomethylating agents (HMAs), patients with myelodysplastic syndromes (MDS) have dismal survival and no approved treatment options. Experimental Design: We conducted a phase 1b investigator-initiated trial of ipilimumab in patients with high-risk MDS that have failed HMAs. Patients received monotherapy at 2 dose-levels (DL; 3 and 10mg/kg) with an induction and a maintenance phase. Toxicities and responses were evaluated with CTCAE.4 and IWG-2006 criteria. We also performed immunologic assays and T-cell receptor sequencing on serial samples. Results: Twenty-nine patients from 7 centers were enrolled. In initial DL1 (3mg) 3 of 6 patients experiencing grade 2-4 immune-related adverse events [IRAEs] that were reversible with drug discontinuation or systemic steroids. On DL2, 4 of 5 patients experienced grade 2 or higher IRAE thus DL1 (3mg/kg) was expanded with no grade 2-4 IRAEs reported in 18 additional patients. Best responses included marrow complete response (mCR) in one patient (3.4%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 7 patients (24% of entire cohort and 29% of those treated with 3mg/kg dose), including 3 patients with more than a year of SD. Five patients underwent allografting without excessive toxicity. Median survival for the group was 294 days (95%CI, 240-671+). Patients who achieved PSD or mCR had significantly higher frequency of T-cells expressing ICOS (Inducible T-Cell CO-Stimulator). Conclusions:Our findings suggest that ipilimumab dosed at 3mg/kg in patients with MDS after HMA failure is safe but has limited efficacy as monotherapy. Increased frequency of ICOS-expressing T-cells might predict clinical benefit.

https://ift.tt/2HJAXvU

Abemaciclib, a Selective CDK4/6 Inhibitor Enhances the Radiosensitivity of Non-Small Cell Lung Cancer in vitro and in vivo

Purpose: To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of CDK4/6 inhibitor, Abemaciclib in Non-Small Cell Lung Cancer cells (NSCLC) in vitro and in vivo. Experimental Design: IR enhancement by Abemaciclib in a variety of NSCLC cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR-induced DNA damage repair was evaluated by -H2AX analysis. Global metabolic alterations by Abemaciclib and IR combination was evaluated by LC/MS mass spectrometry and YSI-Bioanalyzer. Effects of Abemaciclib and IR combination in vivo was studied by xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry. Results: Abemaciclib enhanced the radiosensitivity of NSCLC cells independent of RAS or EGFR status. Enhancement of radiosensitivity was lost in cell lines deficient for functional p53 and RB protein. Post-IR, Abemaciclib treatment inhibited DNA damage repair as measured by -H2AX. Mechanistically, Abemaciclib inhibited RB phosphorylation leading to cell cycle arrest. It also inhibited mTOR signaling and reduced intracellular amino acid pool causing nutrient stress. In vivo, Abemaciclib when administered in an adjuvant setting for the second week post-fractionated IR further inhibited vasculogenesis and tumor re-growth with sustained inhibition of RB/E2F activity, mTOR pathway, and HIF-1 expression. In summary, our study signifies inhibiting CDK4/6 pathway by Abemaciclib in combination with IR as a promising therapeutic strategy to treat NSCLC. Conclusions:Abemaciclib in combination with IR enhances NSCLC radiosensitivity in preclinical models, potentially providing a novel biomarker driven combination therapeutic strategy for patients with NSCLC.

https://ift.tt/2I4bRLz

Fluid Overload in Acute Asthma Exacerbation and Clinical Outcomes. Is There an Association?

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1095-1096, May 1, 2018.


https://ift.tt/2w2qTwz

Identification of Biological Phenotypes in Acute Respiratory Distress Syndrome. From Biomarkers to Clinical Outcome

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1209-1211, May 1, 2018.


https://ift.tt/2I3qwXr

Fluid Balance Is Associated with Clinical Outcomes and Extravascular Lung Water in Children with Acute Asthma Exacerbation

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1128-1135, May 1, 2018.


https://ift.tt/2w2qLgz

Reservations about Permissive Underfeeding in Low versus High NUTRIC Patients?

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1226-1227, May 1, 2018.


https://ift.tt/2rdtUp0

Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis by CXCL16-mediated Effects

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1164-1176, May 1, 2018.


https://ift.tt/2w2qD0z

Intensifying Long-Acting β-Agonist/Corticosteroid Therapy at Acute Exacerbations of Chronic Obstructive Pulmonary Disease

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1096-1098, May 1, 2018.


https://ift.tt/2I3qlvf

Reply to Wijmans et al.: Optical Coherence Tomography: A Valuable Novel Tool for Assessing the Alveolar Compartment in Interstitial Lung Disease?

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1232-1233, May 1, 2018.


https://ift.tt/2w2qt9t

Blood Eosinophilia Neither Reflects Tissue Eosinophils nor Worsens Clinical Outcomes in Chronic Obstructive Pulmonary Disease

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1216-1219, May 1, 2018.


https://ift.tt/2rezTd2

Low-Dose Nocturnal Dexmedetomidine Prevents ICU Delirium. A Randomized, Placebo-controlled Trial

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1147-1156, May 1, 2018.


https://ift.tt/2vYqjje

Reply to Morice and Hart: Increased Propensity for Pneumonia with Fluticasone in Chronic Obstructive Pulmonary Disease

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 9, Page 1230-1231, May 1, 2018.


https://ift.tt/2I7ws1B