.
http://bit.ly/2RTlHFE
Σάββατο 26 Ιανουαρίου 2019
The first hematopoietic stem cell transplantation centre in Iraqi Kurdistan: nursing perspectives and education
Marta Canesi, Chiara Broggi, Kizhan Fazil, Mardin Jafr, Laura Russo, Valentina Panzetti, Gloria Ciabatti, Giulia De Riso, Andrea Mastria and Hiwa Sadiq Sidiq
http://bit.ly/2Sd1hXu
Access to high-cost drugs for advanced breast cancer in Latin America, particularly trastuzumab
Carlos Henrique Barrios, Tomás Reinert and Gustavo Werutsky
http://bit.ly/2Hyksad
Barriers in Latin America for the management of locally advanced breast cancer
Joseph A Pinto, Luis Pinillos, Cynthia Villarreal-Garza, Zaida Morante, Manuel V Villarán, Gerson Mejía, Christian Caglevic, Alfredo Aguilar, Williams Fajardo, Franz Usuga, Marcia Carrasco, Pamela Rebaza, Ana M Posada, Indira Tirado-Hurtado, Claudio Flores and Carlos S Vallejos
http://bit.ly/2S81ueJ
Precision medicine for locally advanced breast cancer: frontiers and challenges in Latin America
Joseph A Pinto, César H Saravia, Claudio Flores, Jhajaira Araujo, David Martínez, Luis J Schwarz, Alberto Casas, Leny Bravo, Jenny Zavaleta, Brigitte Chuima, Hober Alvarado, Ricardo Fujita and Henry L Gómez
http://bit.ly/2HyI4vt
Locally advanced breast cancer in Brazil: current status and future perspectives
Gustavo Werutsky, Paulo Nunes and Carlos Barrios
http://bit.ly/2S2l2RR
Locally advanced breast cancer in young women in Latin America
Cynthia Villarreal-Garza, Edna A Lopez-Martinez, Jose Felipe Muñoz-Lozano and Karla Unger-Saldaña
http://bit.ly/2HAbWro
Triple-negative breast cancer: the reality in Chile and in Latin America
Christian Caglevic, Jaime Anabalón, Cristian Soza, Elizabeth Milla, Fancy Gaete, Ana María Carrasco, Sergio Panay, Carlos Gallardo and Mauricio Mahave
http://bit.ly/2S81X0x
HIF Inhibitors: Status of Current Clinical Development
Abstract
Purpose of Review
In this review, the importance of the hypoxia inducible factor (HIF) pathway in tumorigenesis and cancer treatment outcomes will be discussed. The outcomes of phase II and III clinical trials of direct HIF inhibitors in the treatment of cancer will be reviewed.
Recent Findings
The HIF signaling pathway is activated by tumor-induced hypoxia or by inactivating mutations of the VHL gene. HIF is a transcription factor which regulates the expression of genes involved in adjusting mechanisms to hypoxia such as angiogenesis or apoptosis as well as tumor growth, invasion, and metastasis. The HIF pathway has a key role in development of resistance to different treatment modalities and higher expression of the HIF molecule is associated with poor prognosis.
Summary
Clinical studies of the HIF inhibitors in patients with advanced/refractory cancers suggest benefit and warrant further studies of the HIF inhibitors either as a single agent or in combination with other therapeutic agents.
http://bit.ly/2RPy8lY
Management of Residual Mass in Germ Cell Tumors After Chemotherapy
Abstract
Purpose of Review
The purpose of this review is to educate medical oncologists on the management of patients with residual germ cell tumors and the role of surgical resection after platinum-based chemotherapy.
Recent Findings
Patients with non-seminomatous testicular cancer and residual enlarged retroperitoneal lymph nodes > 1 cm following induction chemotherapy with normal tumor markers should undergo a post-chemotherapy retroperitoneal lymph node dissection. All patients with primary mediastinal non-seminoma should undergo surgical resection of the mediastinal mass post-chemotherapy. These are complex surgeries and require expert surgeons in high-volume centers. Patients with advanced testicular seminoma who have residual masses less than 3 cm after chemotherapy can be observed without further intervention. Patients with a residual mass > 3 cm should be evaluated with PET scan after 6 weeks of chemotherapy. Residual mass with negative PET scan can be followed by surveillance while a positive PET scan requires further work up to rule out active disease.
http://bit.ly/2CRWH7o
Cytokine Release Syndrome With the Novel Treatments of Acute Lymphoblastic Leukemia: Pathophysiology, Prevention, and Treatment
Abstract
Purpose of Review
T cell-based therapies (blinatumomab and CAR T cell therapy) have produced unprecedented responses in relapsed and refractory (r/r) acute lymphoblastic leukemia (ALL) but is accompanied with significant toxicities, of which one of the most common and serious is cytokine release syndrome (CRS). Here we will review the pathophysiology, prevention, and treatment of CRS.
Recent Findings
Efforts have been initiated to define and grade cytokine release syndrome (CRS), to identify patients at risk, to describe biomarkers that predict onset and severity, to understand the pathophysiology, and to prevent and treat severe cases to reduce T cell immunotherapy-related morbidity and mortality.
Summary
Optimizing the timing of T cell-based therapies in ALL, identifying new biomarkers, and investigating novel anti-cytokine agents that have anti-CRS activity are likely to be fruitful avenues of study.
http://bit.ly/2RQ4op3
Deciphering myeloid-derived suppressor cells: isolation and markers in humans, mice and non-human primates
Abstract
In cancer, infection and inflammation, the immune system's function can be dysregulated. Instead of fighting disease, immune cells may increase pathology and suppress host-protective immune responses. Myeloid cells show high plasticity and adapt to changing conditions and pathological challenges. Despite their relevance in disease pathophysiology, the identity, heterogeneity and biology of myeloid cells is still poorly understood. We will focus on phenotypical and functional markers of one of the key myeloid regulatory subtypes, the myeloid derived suppressor cells (MDSC), in humans, mice and non-human primates. Technical issues regarding the isolation of the cells from tissues and blood, timing and sample handling of MDSC will be detailed. Localization of MDSC in a tissue context is of crucial importance and immunohistochemistry approaches for this purpose are discussed. A minimal antibody panel for MDSC research is provided as part of the Mye-EUNITER COST action. Strategies for the identification of additional markers applying state of the art technologies such as mass cytometry will be highlighted. Such marker sets can be used to study MDSC phenotypes across tissues, diseases as well as species and will be crucial to accelerate MDSC research in health and disease.
http://bit.ly/2UfOhOw
A potential role for peripheral natural killer cell activity induced by preoperative chemotherapy in breast cancer patients
Abstract
Tumor-infiltrating lymphocytes are an important prognostic factor after neoadjuvant chemotherapy (NAC) in patients with breast cancer. Natural killer (NK) cells play critical roles in antitumor immune surveillance. Here, we assessed the relationship between peripheral natural killer (pNK) cell activity, tumor microenvironmental factors (TMEFs), and the therapeutic efficacy of preoperative chemotherapy in patients with breast cancer. In a cohort of 39 patients diagnosed with stage II–IV breast cancer who received NAC, we measured pNK cell activity by chromium release assay and assessed TMEF levels by next-generation sequencing. Following NAC, pNK cell activity was increased in 24/39 patients but decreased in 15/39 patients. Increased pNK cell activity following preoperative chemotherapy was associated significantly with the disappearance of axillary lymph node metastasis (Ax+; p = 0.0235). Increased pNK cell activity remained significantly associated with the disappearance of Ax+ in multivariate logistic regression analysis (OR 5.41, 95% CI 1.19–24.52, p = 0.0283). A Grade 2 or higher effect of NAC was associated with high pre-NAC cytotoxic T lymphocyte-associated protein 4 (CTLA-4) levels (p = 0.0281) and elevated post-NAC NK (p = 0.0005) cells and transforming growth factor-beta (TGF-β; p = 0.0350) levels. The disappearance of Ax+ was associated with high pre-NAC CTLA-4 levels (p = 0.0278) and elevated CD4 levels after NAC (p = 0.0250). The systemic activation of pNK cells after NAC may improve metastatic tumor elimination in patients with breast cancer owing to a release from local immunosuppression, and immune activation in the tumor microenvironment.
http://bit.ly/2Hrn1ej
Prognostic value of tumour-infiltrating CD8+ lymphocytes in rectal cancer after neoadjuvant chemoradiation: is indoleamine-2,3-dioxygenase (IDO1) a friend or foe?
Abstract
The prognostic value of the local immune phenotype in patients with colorectal cancer has been extensively studied. Neoadjuvant radiotherapy and/or chemotherapy may potentially influence these immune responses. In this study, we examined the prognostic role of indoleamine-2,3-Dioxygenase (IDO1) and infiltrating cytotoxic T lymphocytes (CD8+) in locally advanced rectal carcinomas after neoadjuvant treatment. Expression of IDO1 and CD8 was evaluated by immunohistochemistry in 106 archival tumour tissue samples from patients following neoadjuvant chemoradiation and radical resection. The average infiltration of IDO1+ and CD8+ cells was calculated along the tumour invasive front, in the tumour centre and within the neoplastic cells and expressed as total scores. Of the tumour specimens evaluable for immunohistochemistry, 100% showed CD8+ lymphocyte infiltration and 93.4% stained positive for IDO1. Total IDO1 score positively correlated with total CD8 score for all three subsites (p = 0.002, Kendall-tau-b 0.357). A high total CD8 score was positively correlated with lower ypUICC-stages (p = 0.047) and lower ypT-categories (p = 0.032). Total IDO1 expression showed a clear trend towards a lower risk of recurrence (p = 0.078). A high total IDO1 score was an independent prognostic marker for prolonged disease-free survival (HR 0.38, p = 0.046) and a high total CD8 score for favourable overall survival (HR 0.16, p = 0.029). Analysis of the local CD8 and IDO1 expression profile may be a helpful tool in predicting prognosis for patients with locally advanced rectal cancer following neoadjuvant chemoradiation.
http://bit.ly/2RJLGzx
Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma
Abstract
Background
Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors' (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients' survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.
Methods
This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan–Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.
Results
A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2–3 (HR 2.57, 95%CI 1.44–4.57; P < 0.01), LDH ≥ 618 IU/L (HR 2.20, 95% CI 1.47–3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35–3.60; P < 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36–0.78; P < 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (P = 0.15). High-grade diarrhea was associated with improved OS (P = 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41–0.76; P < 0.01).
Conclusion
GI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients' OS rates.
http://bit.ly/2W7XPNd
Combining Tumor-Selective Bacterial Therapy with Salmonella typhimurium A1-R and Cancer Metabolism Targeting with Oral Recombinant Methioninase Regressed an Ewing’s Sarcoma in a Patient-Derived Orthotopic Xenograft Model
Background: Ewing's sarcoma (ES) is a recalcitrant disease in need of transformative therapeutics. Objectives: The aim of this study was to investigate the efficacy of tumor-selective Salmonella typhimurium A1-R combined with tumor metabolism targeting with oral administration of recombinant methioninase (o-rMETase), on an ES patient-derived orthotopic xenograft (PDOX) model. Methods: The ES PDOX models were previously established in the right chest wall. The ES PDOX models were randomized into 5 groups when the tumor volume reached 80 mm3: G1: untreated control; G2: doxorubicin; G3: S. typhimurium A1-R; G4: o-rMETase; G5: S. typhimurium A1-R combined with o-rMETase. All mice were sacrificed on day 15. Body weight and tumor volume were assessed twice a week. Results: S. typhimurium A1-R and o-rMETase respectively suppressed tumor growth as monotherapies (p = 0.050 and p = 0.032). S. typhimurium A1-R combined with o-rMETase regressed tumor growth significantly compared to untreated group on day 15 (p #x3c; 0.032). S. typhimurium A1-R combined with o-rMETase group was significantly more effective than S. typhimurium A1-R or o-rMETase monotherapy (p = 0.032, p = 0.032). Conclusions: The present results suggest that the combination of S. typhimurium A1-R and o-rMETase has promise to be a transformative therapy for ES.
Chemotherapy 2018;63:278–283
http://bit.ly/2CRfj7Q
Chemotherapy 2018;63:278–283
http://bit.ly/2CRfj7Q
Association of endothelin receptor type A rs5333 gene polymorphism with steroid response in Egyptian children with idiopathic nephrotic syndrome
Pharmacogenomics, Ahead of Print.
http://bit.ly/2G2S39S
Association between genetic polymorphisms and angiotensin-converting enzyme inhibitor-induced cough: a systematic review and meta-analysis
Pharmacogenomics, Ahead of Print.
http://bit.ly/2FPHyaJ
Polymorphisms in IGF2/H19 gene locus are associated with platinum-based chemotherapeutic response in Chinese patients with epithelial ovarian cancer
Pharmacogenomics, Ahead of Print.
http://bit.ly/2FZXPcu
Ductal carcinoma in situ (DCIS) breast cancer treated with 3-week accelerated hypofractionated whole-breast radiation therapy and concomitant boost
Abstract
Introduction
In patients with ductal carcinoma in situ (DCIS), the clinical outcomes with hypofractionated (HF) whole-breast radiation (WBRT), as well as the role of lumpectomy boost, continue to be evaluated. In this paper, we report our experience on DCIS patients treated with HF WBRT with concomitant boost (CB).
Methods
Early-stage (DCIS, stages I and II) breast cancer patients were treated on an IRB-approved prospective single-arm study with HF WBRT and CB. This study includes only the DCIS subset of patients prescribed a dose of 40.5 Gy × 2.7 Gy per fraction to WB with CB of 4.5 Gy × 0.3G y per fraction over 15 fractions. A total of 107 breasts in 104 patients met the study criteria.
Results
All patients underwent lumpectomy with negative margins. Median age was 59 years. DCIS nuclear grade distribution was 9.3% grade 1, 50.5% grade 2, and 37.4% grade 3. Majority (86%) were ER positive. 41.1% received endocrine therapy. With median follow-up of 74 months (range, 12–158), 5-year actuarial overall survival was 97.2%. At the time of this report, no patient has experienced local relapse. The CTCAE grades 1 and 2 acute skin toxicity was 66.4% and 3.7%, respectively. No patients experienced grade 3 or higher skin toxicity, breast pain, and fatigue.
Conclusion
The HF schedule with CB in DCIS patients is well tolerated and associated with excellent clinical outcomes. This schedule affords the benefit of delivering higher dose to the lumpectomy site without protracting overall treatment time.
http://bit.ly/2B5juwy
Living with and beyond cancer with comorbid illness: a qualitative systematic review and evidence synthesis
Abstract
Purpose
To identify the qualitative evidence on the experience of cancer and comorbid illness from the perspective of patients, carers and health care professionals to identify psycho-social support needs, experience of health care, and to highlight areas where more research is needed.
Methods
A qualitative systematic review following PRISMA guidance. Relevant research databases were searched using an exhaustive list of search terms. Two reviewers independently screened titles and abstracts and discussed variations. Included articles were subject to quality appraisal before data extraction of article characteristics and findings. Thomas and Harden's thematic synthesis of extracted findings was undertaken.
Results
Thirty-one articles were included in the review, covering a range of cancer types and comorbid conditions; with varying time since cancer diagnosis and apparent severity of disease for both cancer and other conditions. The majority of studies were published after 2010 and in high income countries. Few studies focused exclusively on the experience of living with comorbid conditions alongside cancer; such that evidence was limited. Key themes identified included the interaction between cancer and comorbid conditions, symptom experience, illness identities and ageing, self-management and the role of primary and secondary care.
Conclusions
In addition to a better understanding of the complex experience of cancer and comorbidity, the review will combine with research prioritisation work with consumers to inform an interview study with the defined patient group.
Implications for Cancer Survivors
Expanding this evidence base will help to illuminate developing models of cancer patient-centred follow-up care for the large proportion of patients with comorbid conditions.
http://bit.ly/2FQlwEX
Dual cigarette and e-cigarette use in cancer survivors: an analysis using Population Assessment of Tobacco Health (PATH) data
Abstract
Purpose
Cancer survivors who smoke cigarettes face health risks from continued smoking. Some smokers use e-cigarettes to reduce combustible cigarette use, but research on whether cancer survivors do the same is limited. Research is needed to understand whether smokers who are cancer survivors use e-cigarettes at higher rates than smokers never diagnosed with cancer, to inform provider-patient discussions about e-cigarettes.
Methods
Using cross-sectional data from current cigarette smokers in Wave 1 (2013–2014) of the Population Assessment of Tobacco Health (PATH) study, we compared cancer survivors (n = 433) and those without a prior cancer diagnosis (n = 10,872) on e-cigarette use and reasons for use.
Results
Among smokers, 59.4% of cancer survivors and 63.2% of those without a cancer diagnosis had ever used e-cigarettes, and nearly one-quarter of both groups (23.1% and 22.3%, respectively) reported being current users. Multivariate results, however, suggest that cancer survivors might be more likely to be ever (OR = 1.28; p = .05) or current (OR = 1.25; p = .06) e-cigarette users compared to those never diagnosed, although results were marginally significant. The majority of both groups (> 71%) reported using e-cigarettes for perceived health-related reasons—including smoking reduction.
Conclusions
Our study found that among smokers, cancer survivors were using e-cigarettes at similar rates as never-diagnosed smokers and both groups used e-cigarettes largely for perceived health-related reasons.
Implications for cancer survivors
Clinicians who treat cancer survivors may need to routinely ask their patients who smoke about e-cigarette use and address the limited research on the efficacy of e-cigarettes as a cessation aid as compared to other evidence-based options.
http://bit.ly/2G38Sl1
The novel function of tumor protein D54 in regulating pyruvate dehydrogenase and metformin cytotoxicity in breast cancer
Abstract
Background
The role of tumor protein D54 in breast cancer has not been studied and its function in breast cancer remains unclear. In our previous pharmacogenomic studies using lymphoblastoid cell line (LCL), this protein has been identified to affect metformin response. Although metformin has been widely studied as a prophylactic and chemotherapeutic drug, there is still a lack of biomarkers predicting the response to metformin in breast cancer. In this study, we revealed the novel function of TPD54 in breast cancer through understanding how TPD54 altered the cancer cell sensitivity to metformin.
Methods
The role of TPD54 in altering cellular sensitivity to metformin treatment was carried out by either knockdown or overexpression of TPD54, followed by measuring cell viability and reactive oxygen species (ROS) production in MCF7 breast cancer cell line and breast cancer patient-derived xenografts. Functional analysis of TPD54 in breast cancer cells was demonstrated by studying TPD54 protein localization and identification of potential binding partners of TPD54 through immunoprecipitation followed by mass spectrometry. The effect of TPD54 on pyruvate dehydrogenase (PDH) protein regulation was demonstrated by western blot, immunoprecipitation, and site-directed mutagenesis.
Results
TPD54 inhibited colony formation and enhanced cellular sensitivity to metformin treatment in MCF7 cells and breast cancer patient-derived xenografts. Mechanistic study indicated that TPD54 had mitochondrial localization, bound to and stabilized pyruvate dehydrogenase E1α by blocking pyruvate dehydrogenase kinase 1 (PDK1)-mediated serine 232 phosphorylation. TPD54 knockdown increased PDH E1α protein degradation and led to decreased PDH enzyme activity, which reduced mitochondrial oxygen consumption and reactive oxygen species (ROS) production, thus contributing to the resistance of breast cancer cells to metformin treatment.
Conclusion
We have discovered a novel mechanism by which TPD54 regulates pyruvate dehydrogenase and affects the sensitivity of breast cancer to metformin treatment. Our findings highlight the important post-translational regulation of PDK1 on PDH E1α and the potential application of TPD54 as a biomarker for selecting tumors that may be sensitive to metformin therapy. These provide new insights into understanding the regulation of PDH complexes and the resistance mechanisms of cancer cells to metformin treatment.
http://bit.ly/2FRpOvK
A case of pulmonary artery intimal sarcoma successfully treated using concurrent chemoradiotherapy and subsequent chemotherapy
Abstract
Pulmonary artery intimal sarcoma (PAIS) is a rare malignancy with an extremely poor prognosis. A 43-year-old man visited our hospital with shortness of breath and suddenly experienced cardiopulmonary arrest before he could be examined. After prompt resuscitation, we diagnosed PAIS, but the patient refused to undergo surgery because of the high perioperative mortality risk. Thus, the patient was treated using concurrent chemoradiotherapy with weekly paclitaxel therapy, as well as subsequent chemotherapy. The patient continued chemotherapy for 36 months until he elected to discontinue treatment. To the best of our knowledge, this is the first case of PAIS, which is difficult to resect, that was successfully treated using concurrent chemoradiotherapy and subsequent chemotherapy.
http://bit.ly/2G2WS2V
Primary retroperitoneal squamous cell carcinoma: a case report with review of the literature
Abstract
Squamous cell carcinoma originating in the retroperitoneal cavity is an exceedingly rare disease, and little is known about it. Here, we report the case of primary retroperitoneal squamous cell carcinoma. A 76-year-old gravida four para two woman with a history of hysterectomy for unknown reasons was referred to our hospital for an infant-head-sized multicystic pelvic mass. She was initially diagnosed with ovarian cancer Stage IIB, poorly differentiated carcinoma by exploratory laparotomy in which only a tumor biopsy was performed due to severe adhesion. She underwent 5 courses of combination chemotherapy with paclitaxel and carboplatin, which reduced the tumor from 14 to 6.5 cm. Interval debulking surgery proved that the tumor was in the retroperitoneal cavity and not associated with the ovaries. She was finally diagnosed with squamous cell carcinoma originating in the retroperitoneal cavity. Human papilloma virus type 16 was identified using polymerase chain reaction. Three more courses of paclitaxel and carboplatin were administered, and she has been without evidence of disease for 6 months. A comprehensive literature search identified seven similar cases of which four individuals had a history of abdominal hysterectomy. Four out of the seven cases were tested for the presence of P16, two for HPV; all the results were positive. These findings suggest that HPV could be the cause of squamous cell carcinoma on the pelvic peritoneum, and that past hysterectomy is a possible contributing factor.
http://bit.ly/2FRPlVB
Spontaneous regression of a carcinoid tumor that required resection owing to its reappearance and subsequent enlargement after 2 years: a case report
Abstract
We present a rare case of spontaneous regression in a typical lung carcinoid. A 20-year-old woman with an abnormal shadow on a chest radiograph was admitted to our hospital. Computed tomography revealed a smooth nodule in the left S1 + 2 segment. At the 6-month follow-up, the nodule had regressed without treatment. At the 2-year follow-up, the tumor reappeared in the same place as before. We performed left upper lobectomy via 4-port thoracoscopic surgery. A pathological examination revealed a typical carcinoid. Lung carcinoids can spontaneously regress; long-term follow-up is important for timely detection of tumor reappearance.
http://bit.ly/2G1P3dT
Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes
Abstract
Background
In a considerable number of patients with a suspected hereditary tumor syndrome (HTS), no underlying germline mutation is detected in the most likely affected genes. The present study aimed to establish and validate a large gene panel for HTS, and determine its diagnostic yield and clinical utility.
Methods
The study cohort comprised 173 patients with suspected, but unexplained, HTS (group U) and 64 HTS patients with a broad spectrum of known germline mutations (group K). All patients in group U presented with early age at onset, multiple tumors, and/or a familial clustering of various tumor types; no germline mutation had been identified during routine diagnostics. Sequencing of leukocyte DNA was performed for the 94 HTS genes of the Illumina TruSight™Cancer Panel and 54 additional HTS genes.
Results
The sensitivity of the panel to identify known germline variants was 99.6%. In addition to known mutations, a total of 192 rare, potentially pathogenic germline variants in 86 genes were identified. Neither the proportion of rare variants per patient (group K: 0.9 variants; group U: 0.8 variants) nor the proportion of variants in the most frequently mutated, moderately penetrant genes CHEK2 and ATM showed significant inter-group difference. Four of the five patients from group U with a truncating CHEK2 mutation had thyroid cancer, pointing to a broader tumor spectrum in patients with pathogenic CHEK2 variants. In 22% of patients from group K, a further potential causative variant was identified. Here, the most interesting finding was an NF1 nonsense mutation in a child with a known TP53 frameshift mutation. In 17% of patients from group U, potential causative variants were identified. In three of these patients (2%), mutations in PMS2, PTEN, or POLD1 were considered to be causative. In both groups, incidental findings with presumptive predictive value were generated.
Conclusions
The gene panel identified the genetic cause in some prescreened, unexplained HTS patients and generated incidental findings. Some patients harbored predicted pathogenic mutations in more than one established HTS gene, rendering interpretation of the respective alterations challenging. Established moderate risk genes showed an almost equal distribution among patients with known and unexplained disease.
http://bit.ly/2FPnyF7
Posttraumatic Arterial Priapism Treated with Superselective Embolization: Our Clinical Experience and a Review of the Literature
Abstract
Introduction
To present 12 cases of arterial priapism treated by superselective embolization and propose our management algorithm for this condition.
Methods
Between February 2013 and May 2018, 12 cases of arterial priapism caused by blunt trauma were treated by superselective embolization. The mean age of patients was 36 years (25–47 years). All of the patients had normal sexual capability before priapism (IIEF-5 scores 24–25). All patients were treated with superselective embolization after more than 3 weeks of simple conservative treatment had failed. All cases but one used a gelatin sponge as embolic agent. A microcoil was added in one case in which the gelatin sponge failed to occlude the pseudoaneurysm. After superselective embolization, ice pack and "observation" treatments continued. The sexual capability of the patients was evaluated by IIEF-5 scores at 6 months and 12 months postoperatively.
Results
The mean follow-up period was 27.2 months (13–48 months). Three patients achieved complete detumescence immediately. Nine cases needed 2–17 days to return to a flaccid nonpainful state. No patient underwent a second embolization. The time needed to improve erectile function was from 7 days to 4 months. There has been no recurrence. Eleven patients treated with gelatin sponge have normal erectile function, while one patient treated with additional microcoil embolization had mild erectile dysfunction.
Conclusion
Superselective embolization of the fistula is an effective option for arterial priapism. Absorbable agents should be used. Superselective arterial embolization should be considered after 3 weeks of conservative treatment. Patients should undergo another 3 weeks of "observation" treatment before repeated intervention.
http://bit.ly/2G3OQXS
PRDM16 functions as a suppressor of lung adenocarcinoma metastasis
Abstract
Background
The transcription factor PR domain containing 16 (PRDM16) is known to play a significant role in the determination and function of brown and beige fat. However, the role of PRDM16 in tumor biology has not been well addressed. Here we investigated the impact of PRDM16 on tumor growth and metastasis in lung cancer.
Methods
UALCAN database, immunoblotting and immunohistochemistry analysis were used to assess PRDM16 expression in lung cancer patients. Kaplan-Meier plotter database was used to analyze the overall survival of patients with lung cancer stratified by PRDM16 expression. PRDM16 overexpression and knockdown experiments were conducted to assess the effects of PRDM16 on growth and metastasis in vitro and in vivo, and its molecular mechanism was investigated in lung adenocarcinoma cells by chromatin immunoprecipitation-sequencing (ChIP-Seq), real time-quantitative PCR (RT-qPCR), luciferase assay, xenograft models and rescue experiments.
Results
PRDM16 was downregulated in lung adenocarcinomas, and its expression level correlated with key pathological characteristics and prognoses of lung adenocarcinoma patients. Overexpressing PRDM16 inhibited the epithelial-to-mesenchymal transition (EMT) of cancer cells both in vivo and in vitro by repressing the transcription of Mucin-4 (MUC4), one of the regulators of EMT in lung adenocarcinomas. Furthermore, deleting the PR domain from PRDM16 increased the transcriptional repression of MUC4 by exhibiting significant differences in histone modifications on its promoter.
Conclusions
Our findings demonstrate a critical interplay between transcriptional and epigenetic modifications during lung adenocarcinoma progression involving EMT of cancer cells and suggest that PRDM16 is a metastasis suppressor and potential therapeutic target for lung adenocarcinomas.
http://bit.ly/2FQQwVa
MicroRNA-29a activates a multi-component growth and invasion program in glioblastoma
Abstract
Background
Glioblastoma is a malignant brain tumor characterized by rapid growth, diffuse invasion and therapeutic resistance. We recently used microRNA expression profiles to subclassify glioblastoma into five genetically and clinically distinct subclasses, and showed that microRNAs both define and contribute to the phenotypes of these subclasses. Here we show that miR-29a activates a multi-faceted growth and invasion program that promotes glioblastoma aggressiveness.
Methods
microRNA expression profiles from 197 glioblastomas were analyzed to identify the candidate miRNAs that are correlated to glioblastoma aggressiveness. The candidate miRNA, miR-29a, was further studied in vitro and in vivo.
Results
Members of the miR-29 subfamily display increased expression in the two glioblastoma subclasses with the worst prognoses (astrocytic and neural). We observed that miR-29a is among the microRNAs that are most positively-correlated with PTEN copy number in glioblastoma, and that miR-29a promotes glioblastoma growth and invasion in part by targeting PTEN. In PTEN-deficient glioblastoma cells, however, miR-29a nevertheless activates AKT by downregulating the metastasis suppressor, EphB3. In addition, miR-29a robustly promotes invasion in PTEN-deficient glioblastoma cells by repressing translation of the Sox4 transcription factor, and this upregulates the invasion-promoting protein, HIC5. Indeed, we identified Sox4 as the most anti-correlated predicted target of miR-29a in glioblastoma. Importantly, inhibition of endogenous miR-29a decreases glioblastoma growth and invasion in vitro and in vivo, and increased miR-29a expression in glioblastoma specimens correlates with decreased patient survival.
Conclusions
Taken together, these data identify miR-29a as a master regulator of glioblastoma growth and invasion.
http://bit.ly/2G2FCLp
Correction to: EBV-miR-BART8-3p induces epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma cells through activating NF-κB and Erk1/2 pathways
Following publication of the original article [1], the authors reported two errors in the article. In the caption of Figure 1c the sentence "The 20 most highly upregulated EBV BART miRNAs identified between NPC specimens and normal nasopharyngeal mucosal specimens" should be corrected as "The highly upregulated EBV BART miRNAs identified between NPC specimens and normal nasopharyngeal mucosal specimens".
http://bit.ly/2FTiiQM
CXCL12/CXCR4 promotes inflammation-driven colorectal cancer progression through activation of RhoA signaling by sponging miR-133a-3p
Abstract
Background
Activation of CXCL12/CXCR4 axis has been found to be associated with invasion and metastasis in many cancers. However, the underlying mechanism remains elusive. Increasing data highlight that non-coding RNAs are linked to CRC progression.
Methods
The effects of CXCR4 were investigated using villin-CXCR4 transgenic mice model by flow cytometry assay, immunohistochemistry, and Western blot. The mechanism was explored through bioinformatics, luciferase reporter assay and RNA immunoprecipitation assay.
Results
We found that high CXCR4 expression exacerbated colitis-associated cancer in villin-CXCR4 transgenic mice. CXCR4+/−Apcmin/+ compound mutant mice demonstrated higher colorectal tumorigenesis than Apcmin/+ mice. Furthermore, overexpression of CXCR4 was found to promote the epithelial-mesenchymal transition (EMT) and infiltration of myeloid-derived suppressor cells (MDSCs) and macrophages in colonic tissue, accelerating colitis-associated and Apc mutation-driven colorectal tumorigenesis and progression. Notably, miR-133a-3p was found to be significantly decreased in HCT116 cells overexpressing CXCR4 by miRNA sequencing. miR-133a-3p was proved to target RhoA, which is involved in cytoskeletal reorganization that drive cell motility. Importantly, CXCL12/CXCR4-induced upregulation of lncRNA XIST functioned as a ceRNA to sponge miR-133a-3p, thereby liberating the repression of RhoA by miR-133a-3p. The negative correlation of miR-133a-3p with RhoA was also confirmed in human CRC tissues and CXCR4+/− mice.
Conclusions
Our findings revealed the critical role of CXCR4 in promoting progression of inflammatory colorectal cancer through recruiting immunocytes and enhancing cytoskeletal remodeling by lncRNA XIST/ miR-133a-3p/ RhoA signaling. These results provide novel potential therapeutic targets for hindering CXCL12/CXCR4-induced CRC progression.
http://bit.ly/2G38Qtp
Nucleolar and spindle associated protein 1 promotes metastasis of cervical carcinoma cells by activating Wnt/β-catenin signaling
Abstract
Background
The primary obstacle to treat cervical cancer is its high prevalence of metastasis, which severely affects patients' quality of life and survival time. Nucleolar and spindle associated protein 1 (NUSAP1) has been implicated in the development, progression, and metastasis in several types of cancer. However, its oncogenic role in cervical cancer remains unclear.
Methods
Western blot assay and immunohistochemistry were used to determine the expression of NUSAP1 in 21 clinical fresh Cervical cancer tissues and 233 clinicopathologically characterized cervical cancer specimens. The biological roles of NUSAP1 in the metastasis of cervical cancer were investigated both in vitro by EMT, Side population analysis and Transwell assays and so on, and in vivo using a mouse 4w model of hematogenous metastasis and lymph node metastasis. Bioinformatics analysis, luciferase reporter analysis, immunoprecipitation and immunoblotting of nuclear and cytoplasmic cellular fractions were applied to discern and examine the relationshipbetween NUSAP1 and its potential targets.
Results
The results demonstrated that NUSAP1 was upregulated in cervical cancer cells and tissues, correlated positively with metastasis and poor clinical outcome of patients. High expression of NUSAP1 promoted metastasis by enhancing cancer stem cell (CSC) traits and epithelial-mesenchyme transition (EMT) progression, while silencing of NUSAP1 reduced CSC traits and EMT progression. Mechanistically, upregulation of NUSAP1 induced SUMOylation of TCF4 via interacting with SUMO E3 ligase Ran-binding protein 2 (RanBP2) and hyperactivated Wnt/β-catenin signaling in cervical cancer cells. Additionally, NUSAP1-induced cervical cancer cells metastasis and the cancer stem cell phenotype were abrogated with the Wnt/β-catenin signaling inhibitor XAV-939 treatment. Importantly, co-therapy of conventional treatment and XAV-939 will provide a novel and effective treatment for NUSAP1-ovexpressed cervical cancer patients.
Conclusions
Our results demonstrate thatNUSAP1 upregulation contributes to metastasis of cervical cancer by promoting CSC properties and EMT via Wnt/β-catenin signaling and XAV-939 might serve as a potential tailored therapeutic option for patients with NUSAP1-ovexpressed cervical cancer.
http://bit.ly/2FPnCVn
Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors by inhibiting STAT3 pathway
Abstract
Background
Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that rhein has significant antitumor effects, supporting its potential use as an antitumor agent. The IL6/STAT3 signaling pathway has been suggested as an attractive target for the discovery of novel cancer therapeutics.
Methods
The human pancreatic cancer cell lines AsPC-1, Patu8988T, BxPC-3 and PANC-1, and immunodeficient mice were chosen as models to study the effects of rhein. The potent antiproliferative and proapoptotic effects of rhein were examined by cell viability, cellular morphology, apoptosis and colony formation assays. The STAT3 luciferase report assay, immunostaining analysis and Western blot analysis revealed the inhibition of the IL6/STAT3 signaling axis.
Results
Apoptosis was induced by adjunctive use of rhein with epidermal growth factor receptor (EGFR) inhibitors in pancreatic cancer cells as verified by cell apoptosis analysis and changes in the expression level of apoptotic/anti-apoptotic proteins BCL-2, BAX, Caspase 3 and Cl-PARP. Suppression of the phosphorylation of STAT3 and EGFR were also observed as a result of the treatment with a combination of rhein and EGFR inhibitors. Most interestingly, it was found that rhein considerably sensitized cells to erlotinib, thus suppressing tumor growth in PANC-1 and BxPC-3 xenograft models. The in vivo anti-tumor effect was associated with increased apoptosis and combined inhibition of the STAT3 and EGFR pathways in tumor remnants.
Conclusions
Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors through inhibition of STAT3. Taken together, the results indicate that rhein offers a novel blueprint for pancreatic cancer therapy, particularly when combined with EGFR inhibitors.
http://bit.ly/2G2prxw
Mitochondrial transplantation regulates antitumour activity, chemoresistance and mitochondrial dynamics in breast cancer
Abstract
Background
The transfer of whole mitochondria that occurs during cell contact has been found to support cancer progression. However, the regulatory role of mitochondria alone is difficult to elucidate due to the complex microenvironment. Currently, mitochondrial transplantation is an available approach for restoring mitochondrial function in mitochondrial diseases but remains unclear in breast cancer. Herein, effects of mitochondrial transplantation via different approaches in breast cancer were investigated.
Methods
Whole mitochondria (approximately 10.5 μg/ml) were transported into MCF-7 breast cancer cells via passive uptake or Pep-1-mediated delivery. Fresh mitochondria isolated from homeoplasmic 143B osteosarcoma cybrids containing mitochondrial DNA (mtDNA) derived from health individuals (Mito) or mtDNA with the A8344G mutation (Mito8344) were conjugated with cell-penetrating peptide Pep-1 (P-Mito) or not conjugated prior to cell co-culture. Before isolation, mitochondria were stained with MitoTracker dye as the tracking label. After 3 days of treatment, cell viability, proliferation, oxidative stress, drug sensitivity to Doxorubicin/Paclitaxel and mitochondrial function were assessed.
Results
Compared with P-Mito, a small portion of Mito adhered to the cell membrane, and this was accompanied by a slightly lower fluorescent signal by foreign mitochondria in MCF-7 cells. Both transplantations induced cell apoptosis by increasing the nuclear translocation of apoptosis-inducing factor; inhibited cell growth and decreased oxidative stress in MCF-7 cells; and increased the cellular susceptibility of both the MCF-7 and MDA-MB-231 cell lines to Doxorubicin and Paclitaxel. Mitochondrial transplantation also consistently decreased Drp-1, which resulted in an enhancement of the tubular mitochondrial network, but a distinct machinery through the increase of parkin and mitochondrial fusion proteins was observed in the Mito and P-Mito groups, respectively. Furthermore, although there were no differences in energy metabolism after transplantation of normal mitochondria, metabolism was switched to the energetic and glycolytic phenotypes when the mitochondria were replaced with dysfunctional mitochondria, namely, Mito8344 and P-Mito8344, due to dramatically induced glycolysis and reduced mitochondrial respiration, respectively. Consequently, transplant-induced growth inhibition was abolished, and cell growth in the Mito8344 group was even higher than that in the control group.
Conclusion
This study reveals the antitumour potential of mitochondrial transplantation in breast cancer via distinct regulation of mitochondrial function.
http://bit.ly/2FUgkQi
Therapeutic efficacy of a novel βIII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer
Abstract
Background
The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, βIII and βIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available.
Methods
We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of β-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses.
Results
We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, βIII and βIV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth (P < 0.01) in a PanCa xenograft mouse model.
Conclusions
This study has identified an inhibitor of βIII/βIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.
http://bit.ly/2G4yxK3
JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer
Abstract
Background
Human microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically "cold" tumour subtypes characterized by reduced immune cytotoxicity. The molecular linkages between immune-resistance and human MSS CRC is not clear.
Methods
We used transcriptome profiling, in silico analysis, immunohistochemistry, western blot, RT-qPCR and immunofluorescence staining to characterize novel CRC immune biomarkers. The effects of selective antagonists were tested by in vitro assays of long term viability and analysis of kinase active forms using anti-phospho antibodies.
Results
We identified the lymphocyte antigen 6 complex, locus G6D (LY6G6D) as significantly overexpressed (around 15-fold) in CRC when compared with its relatively low expression in other human solid tumours. LY6G6D up-regulation was predominant in MSS CRCs characterized by an enrichment of immune suppressive regulatory T-cells and a limited repertoire of PD-1/PD-L1 immune checkpoint receptors. Coexpression of LY6G6D and CD15 increases the risk of metastatic relapse in response to therapy. Both JAK-STAT5 and RAS-MEK-ERK cascades act in concert as key regulators of LY6G6D and Fucosyltransferase 4 (FUT4), which direct CD15-mediated immune-resistance. Momelotinib, an inhibitor of JAK1/JAK2, consistently abrogated the STAT5/LY6G6D axis in vitro, sensitizing MSS cancer cells with an intact JAK-STAT signaling, to efficiently respond to trametinib, a MEK inhibitor used in clinical setting. Notably, colon cancer cells can evade JAK2/JAK1-targeted therapy by a reversible shift of the RAS-MEK-ERK pathway activity, which explains the treatment failure of JAK1/2 inhibitors in refractory CRC.
Conclusions
Combined targeting of STAT5 and MAPK pathways has superior therapeutic effects on immune resistance. In addition, the new identified LY6G6D antigen is a promising molecular target for human MSS CRC.
http://bit.ly/2FQQsEU
Elevated expression of Gab1 promotes breast cancer metastasis by dissociating the PAR complex
Abstract
Background
Breast cancer (BCa) remains as the second leading cause of cancer-related death in women worldwide. The majority of the deaths are due to its progression to metastatic BCa. Although Grb2-associated binding protein 1 (Gab1) has been implicated in tumor proliferation and metastasis in multiple tumors including colorectal cancer, hepatocellular carcinoma and ovarian cancer, whether and how it regulates BCa metastasis are still poorly understood.
Methods
Western blot assay and immunohistochemical (IHC) staining were performed to assess expression of Gab1 in primary and metastatic BCa clinical samples. Biological function assay studies in vitro and in vivo were employed to investigate the functions of Gab1 during BCa metastasis. Co-immunoprecipitation (co-IP) assessment, western blot assay and immunofluorescence (IF) staining were carried out to investigate the underlying mechanism for the function of Gab1 on BCa metastasis.
Results
In this study, we found that expression level of Gab1 was increased significantly in BCa tissue samples compared to that in benign mammary hyperplastic tissues. Furthermore, elevated expression of Gab1 was positively associated with metastasis in HER2 and TNBC subtypes of BCa. In BCa cell line MDA-MB-231 and SK-BR3 cells, stable overexpression of Gab1 promoted, while knockdown of Gab1 inhibited cell migration in vitro and metastasis in vivo. Mechanistically, overexpression of Gab1 enhanced its interaction with Par3, a key component of the polarity-associated partitioning defective (PAR) complex, leading to a dissociation of the PAR complex. Consequently, dissociated PAR complex induced epithelial-to-mesenchymal transition (EMT) for breast tumor metastasis. By restoration assessment, we found that only re-expression of a fully functional Gab1, but not a mutant Gab1 that harbors either Par3 binding-deficiency or Par1b binding-deficiency, could reverse the repressive phenotype of cell migration in vitro and metastasis in vivo due to Gab1 knockdown.
Conclusions
Our findings indicate that elevated expression of Gab1 promotes BCa metastasis by dissociating the PAR complex that leads to EMT, implicating a role of Gab1 as a potential biomarker of metastatic BCa. Moreover, inhibition of Gab1 expression might be a promising therapeutic strategy for BCa metastasis.
http://bit.ly/2G2ppFU
miR-135b-5p enhances doxorubicin-sensitivity of breast cancer cells through targeting anterior gradient 2
Abstract
Background
The pro-oncogenic anterior gradient 2 (AGR2) is involved in tumor growth and drug resistance of breast cancer. Mechanisms that regulate expression of AGR2 still need to be elucidated.
Methods
In this study, expression levels of AGR2 and miR-135b-5p were analyzed in different breast cancer cell lines as well as in clinical breast cancer tissues. The in vitro and in vivo functional effect of AGR2 and miR-135b-5p were also investigated. A luciferase reporter assay was applied to confirm the interaction between miR-135b-5p and AGR2 mRNA.
Results
We identified AGR2 as a target of miR-135b-5p. Expression of AGR2 was up-regulated in doxorubicin-resistant breast cancer cells. AGR2 mediated doxorubicin-sensitivity of breast cancer cells both in vitro and in vivo. miR-135b-5p negatively regulated AGR2-expression of breast cancer cells increasing doxorubicin-sensitivity. However, miR-135b-5p was down-regulated in doxorubicin-resistant breast cancer cells as well as during treatment with doxorubicin, which might be a probable reason for over-expression of AGR2. Up-regulation of miR-135b-5p increased doxorubicin-sensitivity of breast cancer cells in vivo. In addition, levels of AGR2 negatively correlated with levels of miR-135b-5p in clinical breast cancer tissue samples.
Conclusion
Our results highlight the potential of miR-135b-5p as a target for treating AGR2-expressing breast cancer with doxorubicin-resistance.
http://bit.ly/2Tinkta
ESMO 2018—personal highlights
Summary
This article intends to summarize personal highlights of the ESMO (European Society for Medical Oncology) 2018 meeting and does not aim to give a comprehensive overview. We will summarize the most recent presented data on the treatment of non-small cell lung establishing first-line combinational therapies (chemotherapy backbone with immunotherapy) as standard of care. Furthermore highly practice relevant data on the treatment of recurrent or metastatic head and neck squamous cell carcinoma were presented. Next the treatment landscape of metastatic prostate cancer is changing rapidly and some new aspects in metastatic disease are reported.
http://bit.ly/2Wm0ymn
An update on immunotherapy in breast cancer
Summary
While immunotherapy (IOT) with monoclonal antibodies has long been present in HER2-positive breast cancer, the development of modern IOT concepts such as PD-1/PD-L1 targeting immune checkpoint inhibitors has been slow compared with other malignancies such a melanoma or lung cancer. Recent clinical trials of IOT have focused on triple-negative breast cancer (TNBC) as no specific treatment options beyond chemotherapy have been available in this subtype; in addition, TNBC apparently harbours the largest immunogenic potential. Meanwhile, initial results from the phase III IMpassion130 trial have been presented; here, the addition of atezolizumab to nab–paclitaxel led to a clinically meaningful prolongation of overall survival in the PD-L1 positive subset, potentially defining a novel standard-of-care in the first-line treatment of TNBC. Further evaluation of checkpoint inhibitors alone or in combination with chemotherapy or targeted drugs are currently ongoing in TNBC as well as in other breast cancer subtypes and clinical development is also ongoing in the adjuvant and neoadjuvant settings. This short review summarizes results of recent trials with a focus on clinical outcome data and discusses the ongoing development of IOT in breast cancer.
http://bit.ly/2Rk4ZKs
Role of immune checkpoint inhibitors in gastrointestinal cancer treatment
Summary
In this short review we aim to summarize the role current clinical role of immunotherapy in particular of immune checkpoint inhibition in gastrointestinal malignancies and highlight the most important clinical trials.
http://bit.ly/2WiwCYl
Efficacy of a Novel Intranasal Formulation of Azelastine Hydrochloride and Fluticasone Propionate, Delivered in a Single Spray, for the Treatment of Seasonal Allergic Rhinitis: Results from Russia
Background: The novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP) in a single spray (MP-AzeFlu) was compared with a first-line intranasal antihistamine spray (AZE) in Russian seasonal allergic rhinitis (SAR) patients. Methods: Moderate-to-severe SAR/rhinoconjunctivitis patients (n = 149; aged 18–65 years) were randomized to receive MP-AzeFlu (137/50 μg AZE/FP per spray) or AZE (137 μg/spray), both as 1 spray/nostril twice daily, in a multicenter, open-label, 14-day, parallel-group trial. The primary outcome was change from baseline in morning and evening reflective total nasal symptom score (rTNSS). Secondary end points included: change from baseline in reflective total ocular symptom score (rTOSS), reflective total of 7 symptom scores (rT7SS), 28-item Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) overall score, and EuroQol-5D (EQ-5D) questionnaire score. Results: When compared with AZE-treated patients, those treated with MP-AzeFlu experienced significantly greater reductions in rTNSS (difference: –2.47; 95% confidence interval [CI] –3.65 to –1.30; p #x3c; 0.001), rTOSS (difference: –1.62; 95% CI –2.32 to –0.92; p #x3c; 0.001), and rT7SS (difference: –4.34; 95% CI –5.98 to –2.70; p #x3c; 0.001). Superior relief observed on day 2 with MP-AzeFlu versus AZE was sustained throughout the study. MP-AzeFlu-treated patients experienced a greater improvement in QoL than AZE-treated patients as measured by overall RQLQ score (mean ± SD 2.91 ± 1.08 vs. 2.05 ± 1.15) and EQ-5D score (mean ± SD 87.4 ± 10.3 vs. 83.0 ± 12.8). MP-AzeFlu was well tolerated. Conclusions: MP-AzeFlu was superior to AZE in reducing moderate-to-severe SAR symptoms, providing earlier and more complete symptom relief.
Int Arch Allergy Immunol
http://bit.ly/2Rk4X5i
Int Arch Allergy Immunol
http://bit.ly/2Rk4X5i
Peanut Allergy in Spanish Children: Comparative Profile of Peanut Allergy versus Tolerance
Background: Peanut storage proteins (Ara h 1, Ara h 2, and Ara h 3) have been described as the major peanut allergens in children, although not all peanut-sensitized individuals have clinical reactivity after exposure. Objectives: We studied the sensitization profile of peanut-allergic and peanut-tolerant children in a pediatric cohort. Methods: The clinical features and sensitization profile to the peanut storage proteins Ara h 9 and Pru p 3 were compared between peanut-allergic and peanut-tolerant children using component-resolved diagnostics. Results: Thirty-three peanut-sensitized children were included: 22 allergic and 11 tolerant patients. Seventy-two percent of the peanut-allergic children were sensitized to at least one peanut storage protein. The rates of sensitization to Ara h 1, Ara h 2, and Ara h 3 were 63.6, 68.1, and 68.1%, respectively, among the peanut-allergic children and 27.2, 18.1, and 45.4% among the peanut-tolerant children. IgE from the sera of 18% of the peanut-allergic patients recognized Ara h 9, whereas no sensitization to Ara h 9 was detected in the peanut-tolerant children. A total of 59% of the peanut-allergic and 27% of the peanut-tolerant children were sensitized to Pru p 3. Sensitization to Ara h 1 and Ara h 2 was more frequent among the peanut-allergic children (p #x3c; 0.05). Although the levels of specific IgE against peanut storage proteins were higher in peanut allergy, there were not statistically significantly different from the levels in peanut tolerance, probably due to the small number of patients included. Conclusions: In our population, the peanut-allergic children were mainly sensitized to peanut storage proteins, and Ara h 2 sensitization allows a more accurate diagnosis of clinical reactivity to peanuts. More than half of the peanut-allergic patients were sensitized to peach Pru p 3, and 50% of them had fruit allergy at the time of the study.
Int Arch Allergy Immunol
http://bit.ly/2WmcCDW
Int Arch Allergy Immunol
http://bit.ly/2WmcCDW
Immunotherapy: An Old and New Modality for the Treatment of Cancer
Employing a patient's own immune system for the treatment of cancer has been a promise for more than a century. Antibodies targeting programmed death 1 and other inhibitory receptors expressed on T cells, cancer cells, and other immune cells have demonstrated antitumor activity across solid and hematologic malignancies, leading to a number of approvals by regulatory agencies. These antibodies, also called immune checkpoint inhibitors (ICIs), can achieve durable tumor responses, sometimes lasting several years.
http://bit.ly/2RijDlm
Radiation Therapy and Immune Modulation
Radiotherapy has known immunomodulatory effects and there exists a strong preclinical rationale for combining radiotherapy with immunotherapies. Broadly, the concurrent administration of immunotherapies and radiotherapy does not seem to result in undue toxicity, even when radiotherapy is administered to definitive doses. Recently reported results from prospective clinical trials evaluating radiotherapy/ICB combinations, such as the PACIFIC trial, provide important information on safety and efficacy in the definitive setting and identify potential abscopal effects. This review details the preclinical foundation for the combination of radiotherapy and immunotherapies, summarizes the most recent clinical data available, and highlights active and future areas of study.
http://bit.ly/2WlZ7nZ
Prognostic and Predictive Immunohistochemistry-Based Biomarkers in Cancer and Immunotherapy
Immunotherapy has drastically improved the prognosis of many patients with cancer, but it can also lead to severe immune-related adverse events. Biomarkers, which are molecular markers that indicate a patient's disease outcome or a patient's response to treatment, are therefore crucial to helping clinicians weigh the potential benefits of immunotherapy against its potential toxicities. Immunohistochemistry (IHC) has thus far been a powerful technique for discovery and use of biomarkers such as CD8+ tumor-infiltrating lymphocytes. However, IHC has limited reproducibility. Thus, if more IHC-based biomarkers are to reach the clinic, refinement of the technique using multiplexing or automation is key.
http://bit.ly/2Rijyhy
ITRAQ-Based Quantitative Proteomics Reveals the Proteome Profiles of Primary Duck Embryo Fibroblast Cells Infected with Duck Tembusu Virus
Outbreaks of duck Tembusu virus (DTMUV) have caused substantial economic losses in the major duck-producing regions of China since 2010. To improve our understanding of the host cellular responses to virus infection and the pathogenesis of DTMUV infection, we applied isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with multidimensional liquid chromatography-tandem mass spectrometry to detect the protein changes in duck embryo fibroblast cells (DEFs) infected and mock-infected with DTMUV. In total, 434 cellular proteins were differentially expressed, among which 116, 76, and 339 proteins were differentially expressed in the DTMUV-infected DEFs at 12, 24, and 42 hours postinfection, respectively. The Gene Ontology analysis indicated that the biological processes of the differentially expressed proteins were primarily related to cellular processes, metabolic processes, biological regulation, response to stimulus, and cellular organismal processes and that the molecular functions in which the differentially expressed proteins were mainly involved were binding and catalytic activity. Some selected proteins that were found to be differentially expressed in DTMUV-infected DEFs were further confirmed by real-time PCR. The results of this study provide valuable insight into DTMUV-host interactions. This could lead to a better understanding of DTMUV infection mechanisms.
http://bit.ly/2Bg2Avt
CDX1/2 and KLF5 Expression and Epigenetic Modulation of Sonic Hedgehog Signaling in Gastric Adenocarcinoma
Abstract
Gastric cancer is among the commonplace causes of cancer death worldwide. Sonic hedgehog (Shh) signaling is an important pathway which may be dysregulated in many cancers.CDX1/2, and KLF5are key transcription factors involved in Shh pathway and cancer stem cells. The aim of this study was to investigate the expression and epigenetic alterations of these genes in gastric cancer patients. DNA methylation's modifications of CDX1, KLF5 and CDX2 genes alongside with the expressions of these genes in gastric cancer tissues and their non-tumoral counterparts (margin tissues) were analyzed using methylation specific sequencing, and Real time PCR Taq man assays, respectively. The expression of CDX1 (P = 0.002) and KLF5 (P = 0.010) were decreased significantly, but it was considerably increased for CDX2 (P = 0.001). Relatively, the results for the regulatory region methylation status of each CpG site had shown a notable fluctuation in these genes with no significant difference in most places. The creation of metastatic lymph nodes in patients was significantly associated with increased expression of CDX2 gene. The modifications of these genes expression can be considered as a cancer biomarker in future studies. Methylation of the investigated genes is not the main mechanism of gastric cancer development.
http://bit.ly/2HzSwTD
New Research From Clinical Psychological Science
The Future of Intervention Science: Process-Based Therapy
Stefan G. Hofmann and Steven C. Hayes
The medical illness model, which assumes that symptoms reflect a latent disease that should be targeted with a specific therapy protocol, has been the norm in clinical science, but this seems to be changing. Hoffman and Hayes consider the developments in the field that allow for a move toward process-based therapy (PBT), especially in cognitive-behavioral therapy. A concern for principles and models, with emphasis on the centrality of processes of change along with research identifying moderators and psychological processes, makes this move toward PBT possible. PBT targets the processes responsible for the effectiveness of treatment that are identified theoretically and supported by research. By moving away from the traditional link between treatment protocol and syndrome, clinical science might see a decline in named therapies in favor of procedures linked to processes, a rise of testable models and mediation and moderation studies, as well as a focus on the individual, the context, and new forms of therapeutic relationship and care.
A Return to Functional Analysis, the Search for Mechanisms of Change, and the Nomothetic-Idiographic Issue in Psychosocial Interventions
Gerald C. Davison
Davison comments on Hofmann and Hayes' article on process-based therapy (PBT) in which they suggest the use of functional analysis and PBT in clinical science. PBT targets the processes responsible for the effectiveness of treatment that are supported by theory and research, moving away from the traditional link between treatment protocol and syndrome. Davison provides a historical and conceptual context for Hofmann and Hayes' article and suggests that their views are not new but have been around for more than 60 years. He mentions the importance of change mechanisms in therapy and the departure from simply applying categorized schemes, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and treatment manuals, as well as the challenges of applying general psychological principles to individual cases. Despite considering that Hoffman and Hayes' proposal is not entirely new, Davison suggests that it is important for the development of clinical psychological science to remind researchers and practitioners of the importance of functional analyses.
Process Trumps Protocol: What I Liked About Hofmann and Hayes
Steven D. Hollon
In this commentary, Hollon shows his support for Hofmann and Hayes' urge to move toward process-based therapy (PBT), which targets the processes responsible for the effectiveness of treatment that are identified theoretically and supported by research. PBT allows moving away from the traditional link between treatment protocol and syndrome and allows identifying mediators of the actual processes that underlie behavior. Hollon argues for the importance of identifying these processes for clinical practice rather than relying on protocols. He gives the example of young counselors in India who learned only basic processes instead of full treatment protocols and were able to decrease depression rates and domestic violence among their clients. According to Hollon, this example supports Hofmann and Hayes' proposal for the use of PBT and functional analysis in clinical practice and research.
Commentary on Hofmann and Hayes: The Water Looks Inviting, but How and When Do We Jump in?
Bethany A. Teachman
Teachman comments on the 2018 article by Hofmann and Hayes which noted lack of progress in reducing the burden and prevalence of mental illness, and challenged the clinical field to recognize that empirically supported processes of change should guide treatment planning. Hofmann and Hayes named this solution process-based therapy, in opposition to the usual treatment packages. Teachman discusses questions that will arise in shifting from one-size-fits-all treatment packages to more personalized process-based therapy, and suggests some steps to facilitate this shift. These include the need for more systematic reviews on processes of change, and more investment in processed-based therapy research. Improving access to resources for providers with minimal jargon (e.g., videos, handouts) is another factor that might facilitate the shift to process-based therapy. Teachman also identifies the need to view treatment planning as a dynamic process that should occur with the patients' knowledge and informed consent.
The Promise of a Participatory Approach in Clinical Psychology
Leah Anne Teeters and Sona Dimidjian
Teeters and Dimidjian offer for consideration a participatory approach to Hofmann and Hayes' proposal of using process-based therapy (PBT) instead of category-based therapies (i.e., theories specific for a syndrome). A participatory approach is a set of methods that allows for partnerships among researchers, practitioners, and community members. Participatory approaches usually result in the design and implementation of sustainable interventions. By considering individuals' contexts and cultures, a participatory approach would prevent PBT from becoming overly individualistic and detached from context. Thus, Teeters and Dimidjian propose that clinical psychologists explore the relevance of participatory approaches, which allow for the incorporation of individual and social factors into the design and dissemination of therapeutic processes. Participatory approaches along with Hofmann and Hayes' recommendations will likely accelerate the progress of clinical psychology, they say.
Functional Analysis Is Dead: Long Live Functional Analysis
Stefan G. Hofmann and Steven C. Hayes
Hofmann and Hayes react to the commentaries on their article "The Future of Intervention Science: Process-Based Therapy." Each commentary seemed to agree with their message that clinical interventions must move away from the traditional link between treatment protocol and syndrome and toward process-based treatments (PBTs) targeting the processes theoretically identified and supported by research. Hofmann and Hayes agree that functional analysis and PBT are old ideas but call attention to the fact that research and practice related to these ideas seems to have been stagnant for at least 20 years. The authors also discuss the benefits of considering the social and cultural context of an individual when examining psychological processes. They suggest that research and practice communities are now ready to use functional analysis, intervention science, and PBT to study human complexity.
http://bit.ly/2Tbfh1i
How Psychological Science is Benefiting the World
Technological advances have allowed psychological scientists to measure everything from cognitive impairments to everyday decision-making. Now, the scientists are using their research to inform tools, programs, and interventions that are helping to cultivate a healthier, happier, and more sustainable world.
In a special issue of Perspectives on Psychological Science, a journal of the Association for Psychological Science, more than 25 psychological researchers write about expanding their research beyond academic articles and applying it to the betterment of society and the environment.
"Their work spans ways to make the world a better place by considering individuals, relationships and interactions among people, and broad-scale social and national policies," June Gruber, the journal's interim editor and an assistant professor at University of Colorado Boulder, writes with her associate editors in an introduction to the issue.
Gruber and her colleagues highlight the importance of psychological scientists' involvement in addressing societal challenges, including mental illness, isolation and loneliness, sexual harassment, policies that harm vulnerable refugees, lack of concern for animals, and environmental deterioration. The issue highlights how psychological science has helped disadvantaged youth achieve academic success, improved the efficacy of psychotherapy, helped military officers surmount errors and biases in their decision-making, and fostered peace and reconciliation in ethnic conflicts, among other impacts.
Among the contributors to the issue are some of the world's most eminent scientists.
Albert Bandura, widely described as one of the greatest living psychologists, discusses the use of social cognitive theory to change behaviors and create sustainable social and environmental futures.
Acclaimed psychiatrist Aaron Beck describes how his pioneering work on cognitive behavioral therapy has led to one of the most widely used interventions for increasing individual well-being.
University of Pennsylvania researcher and author Angela Duckworth, known for investigating the science of "grit", examines her path from school teacher to scientist in helping children and adults persist and succeed in the face of challenges.
Stanford University professor Carol Dweck shares how she took her prominent research on mindsets into educational settings and other real-world environments.
Longtime collaborators Kathy Hirsh-Pasek and Roberta Michnick Golinkoff detail their success at designing public spaces to foster learning.
University of Delaware social psychologist James Jones details his research on diversity, race, and racism and his efforts to expand graduate programs for students of color.
Ervin Staub, a well-known researcher on peace and violence, discusses applying his findings to workshops and educational programs for reconciliation in Rwanda.
And organizational researcher and best-selling author Adam Grant calls attention to the importance of disseminating scientific findings to the general public
Gruber and her colleagues say the special issue is intended to inspire future and current scientists who are hoping to make a positive difference in the world.
The issue is available for free to the public online for a short time.
http://bit.ly/2Cy2kra
Potential biomarkers to predict outcome of faecal microbiota transfer for recurrent Clostridioides difficile infection
Faecal microbiota transplantation (FMT) has proven high clinical efficacy in the management of recurrent Clostridioides difficile infection (rCDI) with cure rates of over 80% after a single treatment. Nevertheless, the reasons for failure in the remaining 20% remain elusive. The aim of the present study was to investigate different potential predictors of response to FMT.
http://bit.ly/2Hy2DrL
The Stratified Population Screening of Hereditary Hemorrhagic Telangiectasia
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular disease with a wordwide prevalence of 1:5000–1:10000. We introduce our algorithm for the stratified population screening of HHT. Probands are selected from the consecutive hospital database review for HHT (I7800) and recurrent epistaxis (R0400) and the review of patient records referred by family practicioners. A proportion of probands might be de novo diagnosed with HHT in the 10-year study period. The checkup of probands consists of physical examination, arteriovenous malformation exploration and and genetic testing (ACVRL1 and ENG sequence analysis). The family screening of HHT consists of physical examination and screening for the family-specific mutation of each at-risk individual, and furthermore, arteriovenous malformation exploration in individuals with suspected/definite HHT and/or carrying the mutation. Twenty-five definite HHT patients were explored: 7 of them by the I7800 review, 1 by the R0400 review, 3 were de novo diagnosed, and the remaining 14 were explored by the systematic family screening. Considering the 20 patients alive at the end of the study period and the unavailable 5 potential HHT patients and 12 at-risk family members, the HHT prevalence is estimated to be 1:6090–1:11267 in our study area, implying our algorithm's effectivity in the stratified population screening of HHT.
http://bit.ly/2TflyJl
Circulating androgens and postmenopausal ovarian cancer risk in the Women's Health Initiative Observational Study
Our knowledge of epidemiologic risk factors for ovarian cancer supports a role for androgens in the pathogenesis of this disease; however, few studies have examined associations between circulating androgens and ovarian cancer risk. Using highly sensitive LC‐MS/MS assays, we evaluated associations between pre‐diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case‐control study in the Women's Health Initiative (WHI) Observational Study (OS). We frequency‐matched 169 ovarian cancer cases to 410 controls from women enrolled in WHI‐OS who were not using menopausal hormones at enrollment/blood draw. We estimated associations overall and by subtype (n=102 serous/67 non‐serous) using multivariable adjusted logistic regression. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone‐glucuronide (ADT‐G) and total 5‐α reduced glucuronide metabolites (markers of tissue‐level androgenic activity) were at increased risk of developing non‐serous ovarian cancer: ADT‐G tertile (T)3 versus T1 odds ratio [OR] (95% confidence interval [CI]) 4.36 (1.68‐11.32), p‐heterogeneity 0.002; total glucuronide metabolites 3.63 (1.47‐8.95), 0.002. Risk of developing serous tumors was unrelated to these markers.
ADT‐G and total glucuronide metabolites, better markers of tissue‐level androgenic activity in women than testosterone, were associated with an increased risk of developing non‐serous ovarian cancer. Our work demonstrates that sex steroid metabolism is important in the etiology of non‐serous ovarian cancers and supports a heterogeneous hormonal etiology across histologic subtypes of ovarian cancer.
This article is protected by copyright. All rights reserved.
http://bit.ly/2WeQUlg
DNMT3a‐triggered downregulation of K2p1.1 gene in primary sensory neurons contributes to paclitaxel‐induced neuropathic pain
Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy‐induced neuropathic pain. K2p1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time‐dependently downregulates the expression of K 2p 1.1 mRNA and its coding K2p1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel‐induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 2p 1.1 mRNA is attributed to paclitaxel‐induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel‐induced the decrease of DRG K2p1.1 and mimicking this increase reduces DRG K2p1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 2p 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a‐triggered downregulation of DRG K2p1.1 may contribute to chemotherapy‐induced neuropathic pain.
This article is protected by copyright. All rights reserved.
http://bit.ly/2ReU2tH
Neonatal phototherapy and future risk of childhood cancer
We sought to determine if neonatal phototherapy is associated with a greater risk of childhood cancer. We conducted a retrospective cohort study of 786,998 infants born in hospitals of Quebec, Canada between 2006 and 2016, with 4,660,868 person‐years of follow‐up over an 11‐year period. The exposures were neonatal phototherapy (32,314 or 4.1% of infants) and untreated jaundice (91,855 or 11.7% of infants). The outcome was hospitalization for solid or hematopoietic childhood tumours between 2 months and 11 years of age. We used Cox proportional hazards regression models to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association of phototherapy with childhood cancer, adjusted for infant characteristics. The incidence of childhood cancer was higher for infants with phototherapy (25.1 per 100,000 person‐years) and untreated jaundice (23.0 per 100,000) compared with unexposed infants (21.6 per 100,000). Phototherapy appeared to be associated with late onset solid tumours, including brain/central nervous system cancers. Between age 4 and 11 years, children who received neonatal phototherapy had more than 2 times the risk of any solid tumour compared with unexposed children (HR 2.26, 95% CI 1.34‐3.81). Results were similar for phototherapy compared against untreated jaundice. A similar trend was however less apparent for hematopoietic cancer. We conclude that neonatal phototherapy may be associated with a slightly increased risk of solid tumours in childhood, but cannot rule out an effect of bilirubin. Minimizing unnecessary exposure to phototherapy through adherence to recommended thresholds for treatment is encouraged.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Rf67yZ
Performance of an HPV 16/18 E6 oncoprotein test for detection of cervical precancer and cancer
HPV testing is a better alternative for cervical cancer screening, but additional procedures are required for triage of HPV positive women. HPV encoded oncoproteins E6 and E7, as the main effectors of HPV carcinogenicity represent promising triage alternatives. To evaluate performance of the test, we included 155 women from a screening study and 59 from the same referral population attending colposcopy and with precancerous lesions. All were HPV‐tested with HC2 and genotyped with LiPA, and cervical swabs were tested for HPV16/18 E6 oncoproteins. Histologic specimens were reviewed and adjudicated using p16 immunohistochemistry and 55 women had confirmed histologic HSIL, 31 (56.3%) associated with HPV 16/18, 23 with other HPV types and one HPV negative. Sensitivity and specificity were estimated with histologic HSIL/cancer as gold standard. E6 oncoprotein was detectable in all but one HSIL and in all cancers where HPV16/18 DNA was detected, but in none of the cases associated with other HPV types or HPV negatives. Among the few HPV16/18 DNA positive subjects initially without HSIL (n=4) who were E6 oncoprotein positive, precancer was detected during follow‐up in 2 out of 3 with available information. Estimated sensitivity for HPV16/18‐related HSIL+ was 96.8% (95%CI=83.8‐99.8) and for all HSIL+ regardless of HPV type it was 56.4% (95%CI=43.3‐68.6). Specificity was 97.5% (95%CI=93.7‐99.0). E6 oncoprotein proved as a highly sensitive and specific marker for detection of HPV16/18‐related HSIL lesions in this Honduran population with limited previous screening and may be useful as a triage method in screening programs, particularly in low income countries.
This article is protected by copyright. All rights reserved.
http://bit.ly/2WohqsK
Ethyl-2-amino-pyrrole-3-carboxylates are active against imatinib-resistant gastrointestinal stromal tumors in vitro and in vivo
We showed recently that ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) exhibit potent antiproliferative activities against a broad spectrum of soft tissue sarcoma and gastrointestinal stromal tumor (GIST) cell lines in vitro. The molecular mechanism of action was owing to inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to the accumulation of tumor cells in the M-phase and induction of apoptosis. Given that more than 50% of the patients with GISTs develop resistance to imatinib (IM) over the 2 years of IM-based therapy, we examined whether EAPCs exhibit activity against IM-resistant GISTs in vitro and in vivo. A real-time antiproliferation assay illustrated the potent antiproliferative activities of EAPCs against IM-sensitive and IM-resistant GISTs. This was in agreement with the colony formation assay, which revealed potent antiproliferative activities of EAPCs against IM-resistant GISTs, being much stronger when compared with IM and doxorubicin, a topoisomerase II inhibitor. Next, we tested the efficacy of EAPCs in the xenograft model of GISTs, exhibiting secondary IM resistance owing to RTK switch (loss of c-KIT/gain of FGFR2α). A total of 30 5- to 8-week-old female nu/nu mice were subcutaneously inoculated into the flank areas with IM-resistant GIST-T1-R cells (100 μl of 1×107 GIST T-1R cells/ml suspension, in Dulbecco's PBS). Mice were randomized as control (untreated), IM (50 mg/kg), EAPC-20 (10 mg/kg) or EAPC-24 (10 mg/kg) and were treated orally for 10 days. IM has a minor inhibitory effect on tumor size, thus revealing GIST resistance to IM. In contrast, both of EAPCs effectively reduced the tumor size. This was associated with an increased intratumoral apoptosis as detected by immunohistochemical staining for cleaved caspase-3 on day 5 of the treatment. Furthermore, both EAPCs significantly reduced the proliferative activity of tumor cells in the central zones of tumors as measured by positivity for Ki-67 staining. More importantly, in EAPC-24-treated GISTs, the histological response was mainly characterized by the induction of necrosis, whereas EAPC-20 induced the signs of intratumoral fibrosis and myxoid degeneration. Collectively, our data suggest that EAPC-20 and EAPC-24 are the perspective antitumor agents that exhibit antiproliferative and cytotoxic activity against GISTs exhibiting secondary resistance to IM. Correspondence to Sergei Boichuk, Dr Sci, PhD, MD, Department of Pathology, Kazan State Medical University, Kazan 420012, Russia Tel: +7 917 397 8093; fax: +8 843 236 0652; e-mail: boichuksergei@mail.ru Received September 3, 2018 Accepted January 8, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
http://bit.ly/2UhbhMT
http://bit.ly/2UhbhMT
Cytotoxic constituents from Penicillium concentricum, an endophytic fungus from Trichocolea tomentella
In our continuing effort to identify bioactive secondary metabolites from natural sources, the antiproliferative activity of 23 compounds, previously isolated from Penicillium concentricum, was assessed using the sulforhodamine B assay. The cytotoxic effect was determined against HeLa cervical, HT-29 colon, MDA-MB-321 breast, PC-3, and DU-145 prostate cancer cell lines. Compounds were also tested in the mitochondrial transmembrane potential (MTP) and nuclear factor kappa B (NF-κB) target-based assays. The results showed that 2-bromogentisyl alcohol (2) and 3-hydroxy-benzenemethanol (8) exhibited the highest cytotoxic activity against different cancer cell lines. Epoxydon (14) showed selectivity against DU-145 prostate cancer cells [inhibitory concentration 50 (IC50)=1.2 μmol/l]. Compounds 2, 8, 14, 18, 21 also induced damage of MTP (IC50=0.1, 0.2, 7.0, 9.6, and 1.8 μmol/l, respectively). In the NF-κB assay, only compound 8 exhibited potent inhibition (IC50=0.3 μmol/l). Compounds 2 and 14 showed cytotoxic activity and induction of damage in mitochondrial membrane potential while compound 8 inhibited NF-κB and MTP damage. Additionally, compound 14 with selectivity against DU-145 prostate cancer cells induced cell cycle arrested in G2/M phase. Thus, compounds 2, 8, and 14 could be useful leads in the development of new anticancer agents from natural sources. Correspondence to Esperanza Carcache de Blanco, PhD, Department of Pharmacy, The Ohio State University, Lloyd M. Parks Hall 500 W. 12th Avenue, Columbus, OH 43210, USA Tel: +1 614 247 7815; fax: +1 614 292 1335; e-mail: carcache-de-blan.1@osu.edu Received November 16, 2018 Received in revised form December 26, 2018 Accepted January 16, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
http://bit.ly/2DAUkHJ
http://bit.ly/2DAUkHJ
Confocal Imaging of Double-Stranded RNA and Pattern Recognition Receptors in Negative-Sense RNA Virus Infection
Double-stranded RNA produced during RNA virus replication can be recognized by pattern recognition receptors to induce an innate immune response. For negative-sense RNA viruses, the interaction between the low-level dsRNA and PRRs remains unclear. We have developed a confocal microscopy method to visualize arenavirus dsRNA and PRR in individual cells.
http://bit.ly/2G2q2ze
Assembling Molecular Shuttles Powered by Reversibly Attached Kinesins
We present a protocol to build molecular shuttles, where surface-adhered kinesin motor proteins propel dye-labelled microtubules. Weak interactions of the kinesins with the surface enables their reversible attachment to it. This creates a nanoscale system which exhibits dynamic assembly and disassembly of its components while retaining its functionality.
http://bit.ly/2FPYJZV
An Improved and High Throughput Respiratory Syncytial Virus (RSV) Micro-neutralization Assay
http://bit.ly/2G20C4O
Multi-Modal Home Sleep Monitoring in Older Adults
Here, we present a protocol to improve the quality of data from home sleep testing by providing a method to enhance instructions through a structured participant visit. This protocol includes the implementation of a step-by-step educational manual with photos to ensure proper placement of equipment.
http://bit.ly/2SaHeJp
Isolation and Characterization of Human Umbilical Cord-derived Mesenchymal Stem Cells from Preterm and Term Infants
http://bit.ly/2HGJyUG
Flow Cytometric Detection of Newly-formed Breast Cancer Stem Cell-like Cells After Apoptosis Reversal
Here, we present a protocol to isolate apoptotic breast cancer cells by fluorescence-activated cell sorting and further detect the transition of breast non-stem cancer cells to breast cancer stem cell-like cells after apoptosis reversal by flow cytometry.
http://bit.ly/2RgOKy3
Immunization of Alpacas (Lama pacos) with Protein Antigens and Production of Antigen-specific Single Domain Antibodies
A method for the production of single domain antibodies from alpacas, including immunization, blood collection, B-cell isolation, and selection is described.
http://bit.ly/2WlJbSE
Outcomes of a Multicenter Training Program in Laparoscopic Pancreatoduodenectomy (LAELAPS-2)
Objective: The aim of the study was to assess feasibility and outcomes of a multicenter training program in laparoscopic pancreatoduodenectomy (LPD). Background: Whereas expert centers have reported promising outcomes of LPD, nationwide analyses have raised concerns on its safety, especially during the learning curve. Multicenter, structured LPD training programs reporting outcomes including the first procedures are lacking. No LPD had been performed in the Netherlands before this study. Methods: During 2014–2016, 8 surgeons from 4 high-volume centers completed the Longitudinal Assessment and Realization of Laparoscopic Pancreatic Surgery (LAELAPS-2) training program in LPD, including detailed technique description, video training, and proctoring. In all centers, LPD was performed by 2 surgeons with extensive experience in pancreatic and laparoscopic surgery. Outcomes of all LPDs were prospectively collected. Results: In total, 114 patients underwent LPD. Median pancreatic duct diameter was 3 mm [interquartile range (IQR = 2–4)] and pancreatic texture was soft in 74% of patients. The conversion rate was 11% (n = 12), median blood loss 350 mL (IQR = 200–700), and operative time 375 minutes (IQR = 320–431). Grade B/C postoperative pancreatic fistula occurred in 34% of patients, requiring catheter drainage in 22% and re-operation in 2%. A Clavien-Dindo grade ≥ III complication occurred in 43% of patients. Median length of hospital stay was 15 days (IQR = 9–25). Overall, 30-day and 90-day mortality were both 3.5%. Outcomes were similar for the first and second part of procedures. Conclusions: This LPD training program was feasible and ensured acceptable outcomes during the learning curve in all centers. Future studies should determine whether such a training program is applicable in other settings and assess the added value of LPD.http://bit.ly/2AA6Pla
Using local clinical and microbiological data to develop an institution specific carbapenem-sparing strategy in sepsis: a nested case-control study
From a stewardship perspective it is recommended that antibiotic guidelines are adjusted to the local setting, accounting for the local epidemiology of pathogens. In many settings the prevalence of Gram-negati...
http://bit.ly/2DAGl4A
Orthogonality is superiority in piecewise-polynomial signal segmentation and denoising
Segmentation and denoising of signals often rely on the polynomial model which assumes that every segment is a polynomial of a certain degree and that the segments are modeled independently of each other. Segm...
http://bit.ly/2MFwfCN
PD-L1 expression and its clinicopathological correlation in advanced esophageal squamous cell carcinoma in a Chinese population
Programmed death ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-1), which are targeted by several anti-PD-1 and PD-L1 drugs for a variety of human cancers. However, only a ...
http://bit.ly/2CJzSCY
RRBP1 overexpression is associated with progression and prognosis in endometrial endometrioid adenocarcinoma
Currently, ribosome-binding protein 1 (RRBP1) is considered to be a novel oncogene that is overexpressed in colorectal cancer, lung cancer, mammary cancer, esophageal cancer and other carcinomas. However, the ...
http://bit.ly/2RTcCg8
Potential biomarkers of acute myocardial infarction based on weighted gene co-expression network analysis
Acute myocardial infarction (AMI) is the common cause of mortality in developed countries. The feasibility of whole-genome gene expression analysis to identify outcome-related genes and dysregulated pathways r...
http://bit.ly/2Rjh6aG
Multivariate analysis of genomic variables, effective population size, and mutation rate
The relationship between genomic variables (genome size, gene number, intron size, and intron number) and evolutionary forces has two implications. First, they help to unravel the mechanism underlying genome e...
http://bit.ly/2MyUySJ
High dose gabapentin does not alter tumor growth in mice but reduces arginase activity and increases superoxide dismutase, IL-6 and MCP-1 levels in Ehrlich ascites
The purpose of this study was to evaluate the effect of gabapentin on Ehrlich tumor growth in Swiss mice, a highly aggressive and inflammatory tumor model. Mice were grouped into sets of 5 animals and treated ...
http://bit.ly/2sOqcCv
Influence of sexual maturation status on the relationship between body adiposity indicators and age: a cross-sectional study
To determine the influence of sexual maturation status on adiposity indicators of children and adolescents.
http://bit.ly/2MzdAbJ
Tramadol as an adjunct to intra‐articular local anaesthetic infiltration in knee arthroscopy: a systematic review and meta‐analysis
Background
Arthroscopic knee surgery is a common technique used in Australia. Post‐operative pain is common and can lead to delayed discharge and impair early mobilization. Use of local anaesthesia can reduce pain while avoiding systemic side effects. This systematic review and meta‐analysis aimed to establish the use of tramadol as an adjunct to intra‐articular local anaesthetic infiltration in knee arthroscopy in the current literature.
Methods
Two independent reviewers performed a systematic search of four databases, where 24 articles were identified with six studies (four high‐quality and two low‐quality randomized controlled trials), with a total of 334 patients were included for analysis. RevMan 5.3 software (The Nordic Cochrane Centre, Copenhagen, Denmark) was used to perform the data analysis. The studies included focused on outcomes such as pain scores, breakthrough analgesia, total analgesia, time to discharge and adverse events related to the use of tramadol as an adjunctive therapy.
Results
This study found that using tramadol as an adjunct to intra‐articular local anaesthetic infiltration in arthroscopic knee surgery reduced post‐operative pain and increased time to breakthrough analgesia without an increase in side effects.
Conclusion
This meta‐analysis suggests that tramadol is an efficacious adjunct for use in intra‐articular local anaesthetic infiltration following arthroscopic knee surgery.
http://bit.ly/2RT8sVy
Obesity is a significant risk factor for ileostomy site incisional hernia following reversal
Incisional hernia following ileostomy reversal can cause significant morbidity, impaired quality of life and burden on the healthcare system. Although we found a lower rate of incisional hernias after reversal of ileostomies than reported elsewhere in the literature, it remains a significant clinical problem. Obesity is a significant risk factor for an ileostomy‐site incisional hernia
Background
Incisional hernia following ileostomy reversal can cause significant morbidity, impaired quality of life, and burden on the healthcare system. This study aimed to determine the prevalence of ileostomy site incisional hernia following reversal and to identify possible risk factors for its development.
Methods
This was a retrospective cohort study involving consecutive patients who underwent ileostomy reversal between November 1999 to February 2015 by a single surgeon. Primary outcome analysed was incisional hernia occurrence at the previous stoma site.
Results
Two hundred and twenty‐four ileostomy reversals were identified. The most common indication for ileostomy construction was colorectal cancer, followed by inflammatory bowel disease and diverticulosis. The stomas were either a loop (75%), end‐loop (24%) or end ileostomy (1%). The mean time interval from the stoma creation to reversal was 6.1 months (range 2–69, SD 7.1). After a mean follow‐up of 30.7 months (range 10–89, SD 15.1), 12 patients (5%) developed a hernia at the previous stoma. The mean time for hernia occurrence was 25.2 months (range 3–126, SD 32). Patients who developed ileostomy site incisional hernia were more likely to have a higher body mass index (28.1 versus 26.3, P = 0.007).
Conclusion
Although we found a lower rate of incisional hernias after reversal of ileostomies than reported elsewhere in the literature, it remains a significant clinical problem. Obesity is a significant risk factor for ileostomy‐site incisional hernia.
http://bit.ly/2CLVBdo
Epidemiology and molecular characterization of the re-emerging measles virus among children and adults in the Haut-Ogooue, Gabon
Measles is one of the most infectious diseases with a high mortality rate worldwide. It is caused by the measles virus (MeV) which is a single stranded RNA virus with genetic diversity based on the nucleoprote...
http://bit.ly/2G713uX
Norovirus strain types found within the second infectious intestinal diseases (IID2) study an analysis of norovirus circulating in the community
Norovirus is the commonest cause of infectious intestinal disease (IID) worldwide. In the UK community incidence of norovirus has been estimated at 59/1000 population, equating to four million cases a year. Wh...
http://bit.ly/2FQ1LNC
Improving natural ventilation in hospital waiting and consulting rooms to reduce nosocomial tuberculosis transmission risk in a low resource setting
TB transmission in healthcare facilities is an important public health problem, especially in the often-overcrowded settings of HIV treatment scale-up. The problem is compounded by the emergence of drug resist...
http://bit.ly/2G1RhtV
The respiratory microbiota: new insights into pulmonary tuberculosis
Previous studies demonstrated that the diversity and composition of respiratory microbiota in TB patients were different from healthy individuals. Therefore, the aim of the present analysis was to estimate the...
http://bit.ly/2FU7zpB
How gum disease could lead to Alzheimer's
Researchers find that an oral bacterium usually linked to gum disease also plays a role in Alzheimer's. This finding has led to a new therapeutic approach.
http://bit.ly/2FTttJo
Effects of a Fragmenting Handgun Bullet: Considerations for trauma care providers
Publication date: Available online 25 January 2019
Source: Injury
Author(s): Lynn Hakki, Alison Smith, Jonathan Babin, John Hunt, Juan Duchesne, Patrick Greiffenstein
Abstract
Introduction
Expanding or fragmenting bullets have been known to cause extensive injuries since they became available in the late 19th century. Although these bullets are now banned from international warfare, their use by civilians and law enforcement is still legal in the US. In this case report, we describe the complex injuries and subsequent complicated hospital course of a civilian trauma patient who was shot with a newly-designed fragmenting bullet, known as a Radically Invasive Projectile (RIP) bullet.
Case Report
A 22-year-old man presented as a trauma activation after a gunshot wound to his left chest. He subsequently underwent chest tube placement, an emergent thoracotomy, and an exploratory laparotomy. In the operating room, the patient had multiple ballistic fragments lodged within his left thoracic cavity and left upper abdomen. These fragments caused multiple penetrating injuries resulting in an 18 day hospital stay with numerous complications. He underwent 4 emergency operations, 2 separate admissions to the intensive care unit (ICU), and the placement of 4 chest tubes. He was ultimately discharged home in stable condition.
Conclusion
Expanding or fragmenting bullets are designed to inflict significantly more tissue damage than non-deformable bullets. This type of ammunition is prohibited in international warfare on the basis that it does not serve a military advantage but can result in excessive wounding and unnecessary suffering. There is no such ban for handgun ammunition for domestic use in most countries including the United States. Ammunition manufacturers have recently released a fragmenting bullet that is designed to inflict a maximum amount of tissue damage. In this case report, we described the devestating effects of this bullet on a civilian trauma patient.
http://bit.ly/2S76d0h
Εγγραφή σε:
Αναρτήσεις (Atom)
-
Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
-
heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
-
https://ift.tt/2MQ8Ai8
