LOX and SNAI2 in cancer

Purpose: Epithelial-to-mesenchymal transition (EMT) is important in cancer progression and metastasis. We and others have previously reported that lysyl oxidase (LOX) is overexpressed in aggressive cancers, is associated with increased mortality, and regulates EMT. However, the mechanism by which LOX mediates EMT is unknown. In this study, we investigated the effect of LOX on mediators of EMT. Experimental Design: We used chromatin immunoprecipitation and promoter-luciferase assays to determine the target gene of LOX. To determine the effects of SNAI2 in vivo, we used our metastatic ATC mouse model. To investigate the effects of LOX and SNAI2 on MMPs and TIMPs, protein arrays were used. Primary tumors from patients with metastatic, breast and colon cancer and tissue array for thyroid cancer were assessed for SNAI2 and TIMP4 expression by immunohistochemistry. Results: We found that LOX knockdown decreases SNAI2 expression in cancer cell lines. Furthermore, knockdown of LOX reduced SNAI2 expression in a metastatic mouse model of thyroid cancer. We also demonstrated that LOX binds and transactivates the SNAI2 promoter. We found a direct correlation in thyroid and breast cancer samples between LOX and SNAI2 expression. To understand how LOX/SNAI2 axis mediates these effects, we performed a comprehensive analysis of MMPs/TIMPs. LOX and SNAI2 depletion reduced TIMP4 secretion. Analysis of SNAI2 and TIMP4 expression showed overexpression of both proteins in aggressive thyroid, colon and breast tumors. Conclusions: Our findings provide new evidence that LOX regulates SNAI2 expression and that SNAI2-mediated TIMP4 secretion plays a role in cancer progression.

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GIV as a recurrence marker in stage II colon cancer

Purpose: Prognostic markers that identify patients with stage II colon cancers (CC) who are at risk of recurrence are essential to personalize therapy. We evaluated the potential of GIV/Girdin as a predictor of recurrence risk in such patients. Experimental Design: Expression of full-length GIV was evaluated by immunohistochemistry (IHC) using a newly developed monoclonal antibody together with a mismatch repair (MMR)-specific antibody panel in three stage II CC patient cohorts, ie. a training (n=192), test (n=317), and validation (n=181) cohort, with clinical follow-up data. Recurrence risk stratification models were established in the training cohort of T3, proficient MMR (pMMR) patients without chemotherapy and subsequently validated. Results: For T3 pMMR tumors, GIV expression and the presence of lymphovascular invasion (LVI) were the only factors predicting recurrence in both training (GIV: HR:2.78, p=0.013; LVI: HR 2.54, p=0.025) and combined test and validation (pooled) cohorts (GIV, HR:1.85, p=0.019; LVI, HR:2.52, p=0.0004). A risk model based on GIV expression and LVI-status classified patients into high- or low-risk groups; 3-year recurrence-free survival was significantly lower in the high-risk versus low-risk group across all cohorts (Training: 52.3% versus 84.8%; HR:3.74, 95%CI: 1.50-9.32; Test: 85.9% versus 97.9%, HR:7.83, 95%CI:1.03-59.54; Validation: 59.4% versus 84.4%, HR:3.71, 95%CI: 1.24-11.12). Conclusions: GIV expression status predicts recurrence risk in patients with T3 pMMR stage II CC. A risk model combining GIV expression and LVI-status information further enhances prediction of recurrence. Further validation studies are warranted before GIV status can be routinely included in patient management algorithms.

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Targeting GRP78 in drug resistant myeloma

Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma (MM) and both, its surface expression as well as its biological significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface (s) GRP78 and leads to disease stabilization when used as single-agent in a clinical trial. In this paper, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens. Experimental Design: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of MM. Activity of PAT-SM6 was evaluated in combination with anti-MM agents lenalidomide, bortezomib and dexamethasone in vitro. Finally, we report on a MM patient with relapsed and refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide. Results: Although sGRP78 expression was present at all stages, it increased with disease progression and was even stronger elevated in patients with drug-resistant and extramedullary disease. Pre-treatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-MM effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant MM treated with PAT-SM6, bortezomib and lenalidomide experienced partial remission of both intra- and extramedullary lesions. Conclusions: PAT-SM6 therapy in combination regimens showed efficacy in relapsed refractory MM.

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Prostate cancer glands with cribriform architecture and with glomeruloid features should be considered as Gleason pattern 4 and not pattern 3

Future Oncology Ahead of Print.


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3D tissue-engineered bone marrow: what does this mean for the treatment of multiple myeloma?

Future Oncology Ahead of Print.


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Social media in cancer care: highlights, challenges & opportunities

Future Oncology Ahead of Print.


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Disintegrin and metalloproteinases (ADAMs) expression in gastroesophageal reflux disease and in esophageal adenocarcinoma

Abstract

Background

Clinically useful marker molecules for the progression of gastroesophageal reflux disease and Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) are lacking. Many adenocarcinomas and inflammatory conditions exhibit increased expression of ADAMs, 'a disintegrin and metalloproteinases'.

Methods

We assessed the expression of five ADAMs (9, 10, 12, 17, 19) in three esophageal cell lines (Het-1A, OE19, OE33) by RT-PCR and Western blotting, and in human samples of normal esophagus, esophagitis, BE, Barrett's dysplasia, and EAC by RT-PCR, and in selected samples by immunohistochemistry.

Results

EAC patients showed increased mRNA expression of ADAMs 9, 12, 17 and 19, as compared to controls. At immunohistochemistry, ADAM9 and ADAM10 proteins were increased in EAC. Patient samples also showed increased mRNA expression of ADAM12 in esophagitis, of ADAM9 in BE, and of ADAMs 9, 12 and 19 in Barrett's dysplasia, as compared to controls. Two EAC cell lines showed increased ADAM9 mRNA.

Conclusions

ADAM9 expression is increased in EAC. Its predecessors show increased ADAM9 mRNA expression. The importance of the alterations in ADAM expression for the development of EAC, and their use as marker molecules, warrant further studies.

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Leakage decrease detected by dynamic susceptibility-weighted contrast-enhanced perfusion MRI predicts survival in recurrent glioblastoma treated with bevacizumab

Abstract

Background and purpose

In glioblastoma, tumor progression appears to be triggered by expression of VEGF, a regulator of blood vessel permeability. Bevacizumab is a monoclonal antibody that inhibits angiogenesis by clearing circulating VEGF, resulting in a decline in the contrast-enhancing tumor, which does not always correlate with treatment response. Our objectives were: (1) to evaluate whether changes in DSC perfusion MRI-derived leakage could predict survival in recurrent glioblastoma, and (2) to estimate whether leakage at baseline was related to treatment outcome.

Materials and methods

We retrospectively analyzed DSC perfusion MRI in 24 recurrent glioblastomas treated with bevacizumab as second line chemotherapy. Leakage at baseline and changes in maximum leakage between baseline and the first follow-up after treatment were selected for quantitative analysis. Survival univariate analysis was made constructing survival curves using Kaplan–Meier method and comparing subgroups by log rank probability test.

Results

Leakage reduction at 8 weeks after initiation of bevacizumab treatment had a significant influence on overall survival (OS) and progression-free survival (PFS). Median OS and PFS were 2.4 and 2.8 months longer for patients with leakage reduction at the first follow-up. Higher leakage at baseline was associated with leakage reduction after treatment. Odds ratio of treatment response was 9 for patients with maximum leakage at baseline >5.

Conclusions

Leakage decrease may predict OS and PFS in recurrent glioblastomas treated with bevacizumab. Leakage reduction postulates as a potential biomarker for treatment response evaluation. Leakage at baseline seems to predict response to treatment, but was not independently associated with survival.

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Health-related Quality of Life in Women With Recurrent Ovarian Cancer Receiving Paclitaxel Plus Trebananib or Placebo (TRINOVA-1)

Results from the TRINOVA-1 study of trebananib plus weekly paclitaxel versus placebo plus paclitaxel in women with recurrent ovarian cancer demonstrate that the improvement in PFS among patients in the trebananib arm was achieved without compromising HRQoL.

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Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study

A tailored high-dose oral vitamin D supplementation safely allows a higher percentage of the serum 25OHD level normalization compared with a conventional regimen in chemotherapy-treated early breast cancer patients. As compliance to daily oral supplementation was poor in this setting, other studies are needed to confirm this data. A particular attention should be paid to oral treatment schedule.

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A genomic case study of mixed fibrolamellar hepatocellular carcinoma

We report the first comprehensive genomic analysis of a case of mixed conventional and fibrolamellar HCC (mFL-HCC). This study confirms the expression of DNAJB1:PRKACA, a fusion previously associated with pure FL-HCC but not conventional HCC, in mFL-HCC. These results indicate the DNAJB1:PRKACA fusion has diagnostic utility for both pure and mixed FL-HCC.

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Primary Analysis of a Prospective, Randomized, Single-Blinded Phase II Trial Evaluating the HER2 Peptide AE37 Vaccine in Breast Cancer Patients to Prevent Recurrence

This phase II trial of the AE37 vaccine shows no benefit in the intention to treat population. However, the trial confirms the vaccine to be safe and capable of stimulating an immune response. Prespecified subgroup analyses show the vaccine may reduce the recurrence rate in triple negative breast cancer patients suggesting an appropriate patient population for further clinical investigation.

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Pragmatic Randomized Clinical Trials: A Proposal to Enhance Evaluation of New Cancer Therapies with Early Signs of Exceptional Activity

We propose that for oncology drugs that demonstrate "exceptional activity" in Phase 1 or Phase 2 trials and receive accelerated/conditional approval and/or Breakthrough Therapy Designation, and for certain expanded indications, regulatory authorities should consider accepting data from prospectively-agreed pragmatic randomized clinical trials to grant full regulatory approval.

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Activity of immune checkpoint inhibition in platinum refractory germ cell tumors

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Quality of Life With Palbociclib Plus Fulvestrant in Previously Treated Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Patient-Reported Outcomes From the PALOMA-3 Trial

In treating HR+/HER2– metastatic breast cancer, novel agents that enhance endocrine therapy activity but do not worsen quality of life (QoL) are clinically desired. Patient-reported outcomes data from the PALOMA-3 study suggest palbociclib plus fulvestrant allow patients to maintain good QoL in the endocrine resistance setting while experiencing a substantially delayed disease progression.

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Reply to the letter to the editor "What is the clinical impact of the LUX-Lung 5 trial?" by A. Addeo.

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Perceptions of Urologists About the Conversational Elements Leading to Treatment Decision-Making Among Newly Diagnosed Prostate Cancer Patients

Abstract

Widespread adoption and use of the practice of shared decision-making among health-care providers, especially urologists, has been limited. This study explores urologists' perceptions about their conversational practices leading to decision-making by newly diagnosed prostate cancer patients facing treatment. Semi-structured, in-depth interviews were conducted with 12 community and academic urologists practicing in the St. Louis, MO, region. Data were analyzed using a consensus coding approach. Urologists reported spending 30–60 min with newly diagnosed prostate cancer patients when discussing treatment options. They frequently encouraged family members' involvement in discussions about treatment, especially patients' spouses and children. Participants perceived these conversations to be difficult given the emotional burden associated with a cancer diagnosis, and encouraged patients to postpone their decisions or to get a second opinion before finalizing their treatment of choice. Initial discussions included a presentation of treatment options relevant to the patient's condition, side effects, outcome probabilities, and next steps. Urologists seldom used statistics while talking about treatment outcome probabilities and preferred to explain outcomes in terms of the patient's practical, emotional, and social experiences. Their styles to elicit the patient's preferences ranged from explicitly asking questions to making assumptions based on clinical experience and subtle patient cues. In conclusion, urologists' routine conversations included most elements of shared decision-making. However, shared decision-making required urologists to have nuanced discussions and be skilled in elicitation methods and risk discussions which requires further training. Further research is required to explore roles of family and clinical staff as participants in this process.

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GAB2 promotes cell proliferation by activating the ERK signaling pathway in hepatocellular carcinoma

Abstract

Grb2-associated binding protein 2 (GAB2), a key member of the family of Gab scaffolding adaptors, is important in the phospoinositide3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) signaling pathways, and is closely associated with cell proliferation, cell transformation, and tumor progression. But its role in hepatocellular carcinoma (HCC) is still unknown. In this study, we investigated the expression of GAB2 and its potential clinical and biological significances in HCC. Western bolt and immunohistochemistrical analyses revealed that GAB2 was obviously upregulated in HCC tissues. Meanwhile, GAB2 was significantly associated with histological grade, tumor size, and the proliferation marker Ki-67 through our further analysis. The Kaplan-Meier survival curves also showed that increased GAB2 expression was directly correlated with poor prognosis in HCC patients and served as an independent prognostic marker of overall survival. Moreover, serum starvation-refeeding, RNA interference, CCK-8, EDU, colony formation, and flow-cytometry analyses were all performed with the purpose of investigating GAB2's regulation of HCC cell proliferation. Our results indicated that GAB2 progressively accumulated when cells entered into S phase. Consistently, cell proliferation was distinctly hindered by small interfering RNA. More interestingly, we discovered that GAB2 promoted cell proliferation by enhancing ERK signaling and GAB2-induced cell proliferation was inhibited by the inhibition of ERK activation. Finally, GAB2 was verified to be able to confer doxorubicin resistance in HCC cells. In summary, these data demonstrated that GAB2 might promote HCC cell proliferation by enhancing ERK signaling, and all above findings provided a potential therapeutic strategy for the treatment of HCC.

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Efficient isolation and proteomic analysis of cell plasma membrane proteins in gastric cancer reveal a novel differentiation and progression related cell surface marker, R-cadherin

Abstract

Cell plasma membrane proteins, playing a crucial role in cell malignant transformation and development, were the main targets of tumor detection and therapy. In this study, CyDye/biotin double-labeling proteomic approach was adopted to profile the membrane proteome of gastric cancer cell line BGC-823 and paired immortalized gastric epithelial cell GES-1. Real-time PCR, Western blotting, and immunohistochemical staining were used to validate the differential expression of a novel identified cell surface marker R-cadherin in gastric cancer cells and tissues. Clinicopathological study and survival analysis were performed to estimate its roles in tumor progression and outcome prediction. Real-time PCR and Western blotting showed that the expression level of R-cadherin in gastric cancer were significantly lower than non-cancerous epithelial cell and tissues. Clinicopathological study indicated that R-cadherin was dominantly expressed on cell surface of normal gastric epithelium, and its expression deletion in gastric cancer tissues was associated with tumor site, differentiation, lymph node metastasis, and pTNM (chi-square test, P < 0.05). Those patients with R-cadherin positive expression displayed better overall survivals than negative expression group (log-rank test, P = 0.000). Cox multivariate survival analysis revealed lacking the expression of R-cadherin was a main independent predictor for poor clinical outcome in gastric cancer (RR = 5.680, 95 % CI 2.250–14.341, P < 0.01). We have established a fundamental membrane proteome database for gastric cancer and identified R-cadherin as a tumor differentiation and progression-related cell surface marker of gastric cancer. Lacking the expression of R-cadherin indicates poor prognosis in patients with gastric cancer.

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Epithelioid Hemangioendothelioma: a Rare Primary Thyroid Tumor with Confirmation of WWTR1 and CAMTA1 Rearrangements

Abstract

We report a rare case of epithelioid hemangioendothelioma as a primary thyroid tumor. To our knowledge, there are only two prior unequivocal cases of primary thyroid epithelioid hemangioendothelioma reported in the English literature. This is the first case in the thyroid with molecular confirmation.

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The Independent Effects of Strength Training in Cancer Survivors: a Systematic Review

Abstract

Cancer treatment is associated with adverse changes in strength, body composition, physical function, and quality of life. Exercise training reduces cancer incidence and mortality rates and may offset some of the treatment-related effects. To determine the independent effects of strength training (ST) on the effects of cancer treatment, an initial search was performed in March and then updated in November 2015. Additional articles were identified by scanning references from relevant articles. Studies using traditional ST on strength, body composition, aerobic capacity, functional assessments, and psychosocial parameters were included. Excluded studies had no objective strength measurement or combined ST with additional exercise. Mean and standard deviations from 39 studies across seven cancer types were extracted for main outcomes. ST-induced change scores with 95 % confidence intervals were calculated and were evaluated with paired t tests, where appropriate. Twenty to fifty percent improvements in maximal strength were observed, indicating that the ST programs were effective. Physical function was also enhanced (7–38 %), although gains were less consistent. Body composition and psychosocial changes were rare, with only a few changes in selected cancer types. As such, ST appears to promote benefits that may be specific to cancer types. Strength was the only consistent outcome that improved in all cancer survivors. However, these gains in strength are still of tremendous importance, given its impact on functionality and quality of life. Several practical considerations for exercise testing, training, and data reporting are presented for consideration to improve the overall depth of the field.

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Disintegrin and metalloproteinases (ADAMs) expression in gastroesophageal reflux disease and in esophageal adenocarcinoma

Abstract

Background

Clinically useful marker molecules for the progression of gastroesophageal reflux disease and Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) are lacking. Many adenocarcinomas and inflammatory conditions exhibit increased expression of ADAMs, 'a disintegrin and metalloproteinases'.

Methods

We assessed the expression of five ADAMs (9, 10, 12, 17, 19) in three esophageal cell lines (Het-1A, OE19, OE33) by RT-PCR and Western blotting, and in human samples of normal esophagus, esophagitis, BE, Barrett's dysplasia, and EAC by RT-PCR, and in selected samples by immunohistochemistry.

Results

EAC patients showed increased mRNA expression of ADAMs 9, 12, 17 and 19, as compared to controls. At immunohistochemistry, ADAM9 and ADAM10 proteins were increased in EAC. Patient samples also showed increased mRNA expression of ADAM12 in esophagitis, of ADAM9 in BE, and of ADAMs 9, 12 and 19 in Barrett's dysplasia, as compared to controls. Two EAC cell lines showed increased ADAM9 mRNA.

Conclusions

ADAM9 expression is increased in EAC. Its predecessors show increased ADAM9 mRNA expression. The importance of the alterations in ADAM expression for the development of EAC, and their use as marker molecules, warrant further studies.

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Leakage decrease detected by dynamic susceptibility-weighted contrast-enhanced perfusion MRI predicts survival in recurrent glioblastoma treated with bevacizumab

Abstract

Background and purpose

In glioblastoma, tumor progression appears to be triggered by expression of VEGF, a regulator of blood vessel permeability. Bevacizumab is a monoclonal antibody that inhibits angiogenesis by clearing circulating VEGF, resulting in a decline in the contrast-enhancing tumor, which does not always correlate with treatment response. Our objectives were: (1) to evaluate whether changes in DSC perfusion MRI-derived leakage could predict survival in recurrent glioblastoma, and (2) to estimate whether leakage at baseline was related to treatment outcome.

Materials and methods

We retrospectively analyzed DSC perfusion MRI in 24 recurrent glioblastomas treated with bevacizumab as second line chemotherapy. Leakage at baseline and changes in maximum leakage between baseline and the first follow-up after treatment were selected for quantitative analysis. Survival univariate analysis was made constructing survival curves using Kaplan–Meier method and comparing subgroups by log rank probability test.

Results

Leakage reduction at 8 weeks after initiation of bevacizumab treatment had a significant influence on overall survival (OS) and progression-free survival (PFS). Median OS and PFS were 2.4 and 2.8 months longer for patients with leakage reduction at the first follow-up. Higher leakage at baseline was associated with leakage reduction after treatment. Odds ratio of treatment response was 9 for patients with maximum leakage at baseline >5.

Conclusions

Leakage decrease may predict OS and PFS in recurrent glioblastomas treated with bevacizumab. Leakage reduction postulates as a potential biomarker for treatment response evaluation. Leakage at baseline seems to predict response to treatment, but was not independently associated with survival.

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HPV genotype distribution and anomalous association of HPV33 to cervical neoplastic lesions in San Luis Potosí, Mexico

Abstract

Background

The association of human papillomavirus (HPV) types to neoplastic lesions increase as a function of their oncogenicity and the duration of the infection since lesion severity progresses from low-grade to high-grade and cancer. In an outbreak, the prevalence of the HPV type involved would increase and the proportion of the associated low-grade lesions would predominate over severe lesions. In this study, the prevalence of HPV types and their association to neoplastic lesions was determined in women subjected to colposcopy in San Luis Potosí, Mexico.

Methods

DNA from high-risk (HR) and low-risk (LR) HPV types was identified by E6 nested multiplex PCR in cervical scrapes from 700 women with normal cytology, atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL) or invasive cervical cancer (CC).

Results

Overall HPV-DNA prevalence was 67.7 %, that of HR-HPV was 63.1 %, and that of LR-HPV was 21.3 %. The highest prevalence (78.2 %) occurred in the 15–24 year group, whereas that of single infections was 52 % and that of multiple infections (i.e., by 2–6 HPV types) was 48 %. The most prevalent HR types were HPV33 (33.1 %), HPV16 (16.6 %), HPV18 and HPV51 (6.7 % each). HR-HPV prevalence was 29.6 % in normal cytology, 26.7 % in ASCUS, 63.3 % in LSIL, 68.2 % in HSIL, and 90.5 % in CC. Three prevalence trends for HR-HPV types were found in neoplastic lesions of increasing severity: increasing (LSIL < HSIL < CC) for HPV16, HPV39, HPV18, HPV58, HPV31 and HPV35; asymptotic (LSIL < HSIL ≈ CC) for HPV51 and HPV68; U-shaped (LSIL < HSIL > CC) for HPV33.

Conclusions

Two-thirds of the women subjected to colposcopy from 2007 to 2010 in San Luis Potosí have HPV infections which predominate in the 15–24 years group. Around half of the infections are by one viral type and the rest by 2–6 types. HPV33 is the most prevalent type, followed by HPV16. Overall HR-HPV prevalence increases with the severity of neoplastic lesions. HPV33 prevalence is highest in LSIL and its U-shaped trend with progressing neoplastic lesions differs from the growing/asymptotic trends of other HR-HPV types. An ongoing or recent HPV33 outbreak is consistent with its high prevalence and anomalous association to LSIL.

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Age-related maintenance of eccentric strength: a study of temperature dependence

Abstract

With adult aging, eccentric strength is maintained better than isometric strength leading to a higher ratio of eccentric/isometric force production (ECC/ISO) in older than younger adults. The purpose was to investigate the ECC/ISO during electrical activation of the adductor pollicis during lengthening (20–320° s⁻¹) contractions in 24 young (n = 12, ∼24 years) and old (n = 12, ∼72 years) males across muscle temperatures (cold ∼19 °C; normal ∼30 °C; warm ∼35 °C). For isometric force, the old were 20–30 % weaker in the normal and cold conditions (P < 0.05) with no difference for the warm condition compared to young (P > 0.05). Half-relaxation time (HRT) did not differ across age for the normal and warm temperatures (P > 0.05), but it slowed significantly for old in the cold condition compared with young (∼15 %; P < 0.05), as well, there was a 20 and 40 % increase in muscle stiffness for the young and old, respectively. ECC/ISO was 50–60 % greater for the cold condition than the normal and warm conditions. There was no age difference in ECC/ISO across ages for the normal and warm conditions (P > 0.05), but for the cold, the old exhibited a 20–35 % higher ECC/ISO than did the young for velocities above 60° s⁻¹ (P < 0.05). A contributing factor to the elevated ECC/ISO is an increased proportion of weakly compared to strongly bound crossbridges. These findings highlight the relationship (r = 0.70) between intrinsic muscle contractile speed (HRT) and eccentric strength in old age.

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Dental Care for Survivors of Adolescent and Young Adult Cancer: Special Considerations

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


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Nutritional Requirements of Pancreatic Cancers - A Conversation with Dafna Bar-Sagi

Editor's Note: Dafna Bar-Sagi is Professor in the Departments of Biochemistry & Molecular Pharmacology and Medicine, and Senior Vice President and Vice Dean for Science at New York University's School of Medicine. In 1986 Dr. Bar-Sagi and her postdoc advisor, Dr. James Feramisco, observed that injection of oncogenic KRAS protein into fibroblasts caused morphological changes, including pronounced membrane ruffling and the accumulation of pinocytic vesicles. Recent investigations into the metabolism of cancers, especially cancers driven by mutant KRAS, have transformed macropinocytosis from a phenotypic curiosity to a key player in the nutrition of pancreatic cancer cells. RAS Central editors recently interviewed Dr. Bar-Sagi about her science and her career.

Can you describe where you were, what you were doing, and what your position was when you first observed macropinocytosis induced by RAS protein? I was a fairly new postdoc in Jim Feramisco's lab at Cold Spring Harbor. It was a cell biology lab that had essentially transformed itself into a cancer biology group with all of the excitement about the discovery of oncogenes, particularly RAS. We wanted to understand what RAS was doing—how the transfection of a piece of DNA encoding RAS into NIH3T3 cells caused them to become transformed. The challenge we faced was that it took up to 3 weeks from the time NIH3T3 cells were transfected with a mutant RAS gene to when we saw them form foci. Lots of other things might have happened over that time, many of which were probably secondary or tertiary consequences of having RAS in the cells.

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Erratum to: In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

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Report of diabetes mellitus remission in a cat by orally administered glibenclamide

Abstract

Clinical remission of diabetes mellitus which is one of the most commonly encountered endocrine diseases in cats is not very frequent. A 3-year-old male castrated Russian Blue cat with a history of excessive water intake and urination as well as weight loss, lethargy, and unkempt hair coat was referred to us. Type 2 diabetes mellitus was diagnosed based on clinical signs of laboratory findings in this cat. The cat was completely treated in six weeks by orally administered glibenclamide. Based on previously reported studies many factors are involved in the remission of diabetes. Most of these are due to the possibility of reversal of glucotoxicity with insulin injections or orally administered sulfonylurea drugs associated with a reduction of carbohydrates in the diet. The animal subject was monitored for 1 year after remission. The cat was normal in blood glucose after each follow-up. To the best of the authors' knowledge, this clinical description is the first report of remission in a cat with type 2 diabetes mellitus by glibenclamide in the veterinary literature reported from Iran.

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Polyphenolic contents and antioxidant activities of two medicinal plant species, Mentha piperita and Stevia rebaudiana , cultivated in Iran

Abstract

Mentha piperita (peppermint) and Stevia rebaudiana (stevia) are now widespread in cultivation worldwide. However, reports about the contents of these two plant species are scarce. To establish the polyphenolic contents and antioxidant activity of these plants by ferric ion-reducing activity (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) methods, local plants were harvested in flowering stage. Samples without any previous treatments were analyzed using high-performance liquid chromatography (HPLC) to determine the polyphenolic contents. Also, their antioxidant properties were determined using FRAP and DPPH methods. Six phenolic compounds including quercetin, p-coumaric acid, trans-ferulic acid, hesperidin, hesperetin, and rosmarinic acid were identified and quantified in peppermint. However, hesperidin, eugenol, coumarin, and vanillin were the most component in stevia. Peppermint showed better antioxidant properties than stevia in both FRAP and DPPH assessments. Our findings demonstrated that these two plants contain high polyphenolic compounds and are potent antioxidant species. Further studies on the therapeutic properties of these plants in animal and human models of diseases are recommended.

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Porcine circovirus type 2 expression in the brain of neonatal piglets with congenital tremor

Abstract

The present study demonstrates the presence of porcine circovirus type 2 (PCV2) antigen in the brains of neonatal piglets with congenital tremor. Piglets with clinical signs of congenital tremor were collected from a commercial swine herd for post-mortem examination. Brain tissue was collected from the piglets and was fixed in 10 % neutral buffered formalin, embedded in paraffin, and 4-μm thick sections were obtained. The PCV2 antigens were identified in the paraffin-embedded brain tissue sections by immunohistochemistry and light microscopy. The piglet preweaning mortality rates from birth to 14 and 21 days of age were 24.1 and 27.6 %, respectively. No typical gross lesions of PCV2 infection were observed in any of the piglets; however, PCV2 DNA was detected in the heart of a piglet. Immunostaining of PCV2 antigen was detected in neurons throughout the brain. It can be concluded that PCV2 antigen is present in the brain tissue of neonatal piglets with congenital tremor. Additional studies are required to determine the association between PCV2 expression and brain function.

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Evaluation of hepatic markers and body weight gain in growing and finishing steers

Abstract

Background

The liver plays an important role in nutrient metabolism, in detoxification and excretion of hydrophobic metabolites, and in the synthesis of most circulating proteins. Thus, enhanced knowledge of the processes that regulate liver function in beef cattle production stages can lead to significant improvements in their management.

Aims

The authors studied the levels of some serum liver parameters during growing and finishing stages of steers.

Methods

Blood samples were collected from (n = 60) steers at day 1 and at day 21 and 42 days after the start of the growing (group 1 n = 30: mean body weight (BW) 430 ± 5.8 Kg) or finishing (group 2 n = 30: mean BW 591 ± 5.3 Kg) phases. Steers from both groups were separated into two subgroups (A and B, respectively) according to the percentage of body weight gain (%WG). Subgroup A steers had a lower mean %WG than subgroup B steers. Serum total proteins (TP), albumin, globulins, serum urea nitrogen (SUN), total and conjugated bilirubin (TB, CB), aspartate amino transferase (AST), and gamma-glutamyltransferase (GGT) were assessed in order to evaluate significant differences between groups and subgroups.

Results

All parameters showed significant differences between the phases and between groups with the exception of AST and GGT. Mean ± S.D. of %WG was 11.07 ± 1.95 for group 1 and 9.84 ± 0.77 % for group 2. For group 1 steers, there was a significant difference on SUN concentration and GGT activity between subgroup A and subgroup B.

Conclusions

These findings suggest that hepatic markers in steers are influenced by production stages and improve the knowledge about the effect of growing and finishing phases on their hepatic markers. Furthermore, it underlies the importance of monitoring body weight gain in order to obtain a maximizing profitability.

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A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors

Abstract

Purpose

VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.

Methods

VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response.

Results

Nine patients were treated across three dose levels (200–600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer).

Conclusions

VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

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Stereotactic body radiation therapy for low and intermediate risk prostate cancer—Results from a multi-institutional clinical trial

Publication date: May 2016
Source:European Journal of Cancer, Volume 59
Author(s): Raquibul Hannan, Vasu Tumati, Xian-Jin Xie, L. Chinsoo Cho, Brian D. Kavanagh, Jeffrey Brindle, David Raben, Akash Nanda, Susan Cooley, D.W. Nathan Kim, David Pistenmaa, Yair Lotan, Robert Timmerman
BackgroundWe report the outcome of a phase I/II clinical trial of stereotactic body radiation therapy (SBRT) for low (LR) and select intermediate risk (IR) prostate cancer (PCa) patients.Patients and methodsEligible patients included men with prostate adenocarcinoma with Gleason score 6 with PSA ≤ 20 or Gleason 7 with PSA ≤ 15 and clinical stage ≤ T2b. For the phase I portion of the study patients in cohorts of 15 received 45, 47.5, or 50 Gray (Gy) in five fractions. Since the maximally tolerated dose was not met in the phase I study, an additional 47 patients received 50 Gy in five fractions in the phase II study. Toxicity using Common Toxicity Criteria for Adverse Events v. 3.0, quality of life, and outcome data was collected.ResultsA total of 91 patients are included for analysis; 63.7% had NCCN IR and 36.3% had LR PCa. At a median follow up of 54 months the actuarial freedom from biochemical failure was 100% at 3 years and 98.6% at 5 years. Actuarial distant metastasis free survival was 100% at 3 and 5 years. Overall survival was 94% at 3 years and 89.7% at 5 years with no deaths attributed to PCa. Acute and late urinary grade ≥ III toxicity occurred in 0% and 5.5% of patients, respectively. Gastrointestinal (GI) acute and late toxicity of grade ≥ III occurred in 2% and 7% of patients, respectively. A total of four men experienced grade IV toxicity (three GI, one genitourinary).ConclusionSBRT treatment results in excellent biochemical control rates at 5 years for LR and IR PCa patients although doses greater than 47.5 Gy in five fractions led to increased severe late toxicity.



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