Biomarkers in Graft-Versus-Host Disease: from Prediction and Diagnosis to Insights into Complex Graft/Host Interactions

Abstract

Purpose of Review

Acute graft versus host disease (aGVHD) is a frequent cause of treatment-related mortality after allogeneic hematopoietic stem cell transplantation (alloHCT), with few effective treatment options beyond systemic steroids. Discovery of biomarkers for aGVHD may provide insight into the pathophysiology of aGVHD and suggest novel mechanisms for treatment.

Recent Findings

We highlight biomarkers within innate immune activation, T-cell-mediated tissue damage, endothelial damage, dysbiosis, and poor wound healing that can be obtained prior to transplant, in the early transplant period, or at the onset of aGVHD.

Summary

aGVHD biomarkers have predictive and prognostic utility but also suggest novel mechanisms of recipient tissue damage and impaired regenerative capacity. These mechanisms should be further studied and tested in therapeutic clinical trials to improve outcomes post-alloHCT.

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In reply:

We thank Dr. Frei for his interest in our study. Unfortunately, we are not in the position to completely defend the original power analysis for 2 reasons: Dr. Homel, who was the statistician for our study, died suddenly soon after completing this work. In retrospect, his wording concerning significant clinical difference of 1.3 units among 3 groups is somewhat unclear, so we cannot now exactly explain or justify his method. We reiterate here that we characterize this study as an equivalence trial.

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A Commentary: Do α2-Adrenergic Agonists Decrease the Symptoms Associated With Opioid Withdrawal?

We read with interest the recent article by Gottlieb and Gore,1 which presented a synopsis of the Cochrane systematic review by Gowing et al.2 We have concerns that this article overstates the effects of α-agonist therapies.

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Best Save for Retirement

It was a typical busy shift in the ED. I was finishing up with a patient in the ENT room when the nurse opened the door.

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Man With Chest Pain and Lump in Neck

A 44-year-old man with a history of coronary artery bypass graft 1 year previously presented to the emergency department with substernal chest pain and a painful lump at the base of his neck (Figure 1), noted the day before presentation after he completed push-ups. The lump at the base of the neck was noted to be more prominent and painful when the patient turned his head to the left.

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In reply:

We thank you for your insightful comments with respect to the appropriate treatment and management of opioid withdrawal in the emergency department (ED) setting. We agree with Drs. Flemming and Hoffman in regard to the importance of appropriate referral and follow-up after presentation for acute opioid withdrawal. Given the associated pharmacologic and psychological components of opioid addiction, we believe that this is an important part of the treatment plan that deserves proper attention.

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Adolescent With a Non-Healing Thigh Injury

A 13-year-old girl presented to the emergency department (ED) with a 3-week history of a "weeping wound" on her right medial thigh. Three months before, she fell off a horse and obtained a saddle injury to her right medial thigh, with extensive bruising and swelling. She initially presented to an outside ED, where radiographs were negative for fracture and venous ultrasonography was negative for thrombosis. Three weeks before the current ED visit, she developed an erythematous wound with yellow drainage (Figure 1).

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Short Expiration Dates May Exacerbate Drug Shortages

Every week emergency physician James Augustine, MD, collects the list of medications that suppliers are running short on and passes the information along to his emergency medical services (EMS) and emergency medicine colleagues. Each week, the list keeps getting longer.

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Choosing Sunshine

Just after lunch, I was summoned to the bedside of a cancer patient who had just arrived in the ED. The resident told me Mark had refractory metastatic melanoma. Even the newer immunotherapies had failed him. Still, his talented oncologist had managed to coax him through complication after complication. As a result, the ED folks knew Mark well, and they were worried about how he looked this time. Now, seeing signs of overwhelming infection, the intensivists were nervous too. They were milling about looking at x-rays and labs, muttering about code status.

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Improving the Quality of Emergency Care for Transgender Patients

SEE RELATED ARTICLES, P. 170, 183.

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Man With Bumps on His Shin

A 37-year-old man presented to the emergency department with "bumps" that had been present on his right shin for 2 months. The papular rash spread over the anterior lower leg and was very pruritic. There was no known exposure to irritants, allergens, or infectious agents. A 10×20-cm area of hyperpigmented papules that coalesced was present at the anterior right shin, with some excoriations (Figure 1). The edges were well demarcated, without tenderness or purulence. No ulcerations, erosions, or other dermatoses were present (Figure 2).

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Risk Stratifying Febrile Infants: A Moving Target

SEE RELATED ARTICLE, P. 211.

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In reply:

We appreciate Dr. Heller's thoughts and would like to address his concerns in regard to our conclusions. He is correct when he points out that ketorolac administration follows linear pharmacokinetics. We also concur that the duration of analgesia conferred by ketorolac differs according to the size of the dose, which is indeed an important factor when considering successful pain management beyond the emergency department (ED) stay.1

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Annals Q&A With Dr. Raul Ruiz

In October 2017, during the American College of Emergency Physicians' Scientific Assembly, Annals News & Perspective Associate Editor Jeremy Faust, MD, sat down for an interview with Raul Ruiz, MD, (D-California, 36th District) in his office on Capitol Hill. Currently, Dr. Ruiz is the only emergency physician in the United States Congress. He was elected to the House of Representatives in 2012 and is currently serving his third term.

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15 Rounds

15 rounds across a streetlet loose to fly for reasons lost to you and Iand aimed at no specific threat exceptone boy who lived on that small slipstuck out his neck by lousy luck into its gripand there a bullet found a path so soft and warmit slipped right in and out across andmissed by hairs the wispy strands of nervethe stringy spinal cordjust past the rock hard bones of spineand stretchy sheaths that course with bloodand out below the matter of his mindthe pink and gray and squishy stuff wheresouls are housed and thoughts arise.

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Clinical Decision Aids or Clinician Gestalt? Hard to Know Which Is Better

Q1. The goal of this investigation is to "determine how often studies that evaluate the performance of an aid for decisionmaking…compare the aid's performance to independent unaided physician judgment."1

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Hyperactive Child With Chest Pain

A previously healthy 9-year-old boy with a diagnosis of attention deficit and hyperactivity disorder presented to the emergency department with a 1-hour history of chest pain and dysphagia. On physical examination, he could swallow and manage his secretions. He had no reproducible chest pain, and his breath sounds were clear bilaterally. Chest radiograph was obtained (Figures 1 and 2).

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Global Research Highlights

Editor's note: Annals has partnered with a small group of selected journals of international emergency medicine societies to share from each a highlighted research study, as selected monthly by their editors. Our goals are to increase awareness of our readership to research developments in the international emergency medicine literature, promote collaboration among the selected international emergency medicine journals, and support the improvement of emergency medicine world-wide, as described in the WAME statement at http://ift.tt/2dmKsCb.

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Classified

FLORIDA, Port Charlotte: Stable, 22 year old, progressive independent group seeking residency trained, board certified EM physicians for expansion to second facility. 27k and 22k volume EDs. Full specialty backup. Excellent compensation based on productivity with full time income potential exceeding 350k. Flexible scheduling. Documentation by EMR. Malpractice, Health Insurance, Dental provided. Located on Charlotte Harbor with saltwater access to the Gulf. Short drive to Tampa, Sarasota, Fort Myers, Naples.

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Table of Contents

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Male With Sore Throat

A 26-year-old man presented to our emergency department, complaining of a sore throat. The patient had recently received a diagnosis of mononucleosis. He later developed a rash, for which he presented to another hospital, but was discharged home. He then presented to our hospital 3 days later, complaining of a severe sore throat and inability to tolerate solid foods. Physical examination result was remarkable for a skin eruption consisting of violaceous nodules covering his face, tonsils, and mucus membranes (Figure).

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Body Image of Highly Trained Female Athletes Engaged in Different Types of Sport

Background. The aim of the study was to evaluate differences in body image across different types of sports in highly trained female athletes. Methods. 242 female individuals, aged 13–30 years (, SD = 4.5), representing aesthetic sports () and nonaesthetic sports (), were recruited from different sports clubs in Poland. Body image, BMI, age, the level of competition attained, and the training background of participants were recorded. Results. One-way ANOVA showed differences in the body image of athletes engaged in different types of sport (, , and ). The model predicting the body image of female athletes was significant (, ); the adjusted . Type of sport explained 7.1% (, ), age explained 4.5% (), BMI explained 3.6% (), and level of competition explained 0.9% (, ) of variance in body image. Conclusions. The findings provide vital new knowledge which can be used by researchers and practitioners in designing educational programs on weight-related behaviors in female athletes. Such programs should be implemented especially in young female athletes participating in high-level sporting activities at an early stage.

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Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways

Glioblastoma multiforme (GBM) is one of the most devastating brain tumors with median survival of one year and presents unique challenges to therapy because of its aggressive behavior. Current treatment strategy involves surgery, radiotherapy, immunotherapy, and adjuvant chemotherapy even though optimal management requires a multidisciplinary approach and knowledge of potential complications from both the disease and its treatment. Thymoquinone (TQ), the main bioactive component of Nigella sativa L., has exhibited anticancer effects in numerous preclinical studies. Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteract carcinogenesis, malignant growth, invasion, migration, and angiogenesis. TQ can specifically sensitize tumor cells towards conventional cancer treatments and minimize therapy-associated toxic effects in normal cells. Its potential to enter brain via nasal pathway due to volatile nature of TQ adds another advantage in overcoming blood-brain barrier. In this review, we summarized the potential role of TQ in different signaling pathways in GBM that have undergone treatment with standard therapeutic modalities or with TQ. Altogether, we suggest further comprehensive evaluation of TQ in preclinical and clinical level to delineate its implied utility as novel therapeutics to combat the challenges for the treatment of GBM.

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Comparing Different Recording Lengths of Dynamic Cerebral Autoregulation: 5 versus 10 Minutes

We compared the dynamic cerebral autoregulation (dCA) indices between 5- and 10-minute data lengths by analyzing 37 patients with ischemic stroke and 51 controls in this study. Correlation coefficient () and transfer function analysis were applied for dCA analysis. and phase shift in all frequency bands were not significantly different between 5- and 10-minute recordings [mean difference: = 0.02; phase shift of very low frequency (0.02–0.07 Hz) = 0.3°, low frequency (0.07–0.20 Hz) = 0.6°, and high frequency (0.20–0.50 Hz) = 0.1°]. However, the gains in all frequency bands of a 5-minute recording were slightly but significantly higher than those of a 10-minute recording (mean difference of gain: very low frequency = 0.05 cm/s/mmHg, low frequency = 0.11 cm/s/mmHg, and high frequency = 0.14 cm/s/mmHg). The intraclass correlation coefficients between all dCA indices of 5- and 10-minute recordings were favorable, especially in (0.93), phase shift in very low frequency (0.87), and gain in very low frequency (0.94). The areas under the receiver operating characteristic curve for stroke diagnosis between 5- and 10-minute recordings were not different. We concluded that dCA assessed by using a 5-minute recording is not significantly different from that using a 10-minute recording in the clinical application.

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Revealing the Amylase Interactome in Whole Saliva Using Proteomic Approaches

Understanding proteins present in saliva and their function when isolated is not enough to describe their real role in the mouth. Due to protein-protein interactions, structural changes may occur in macromolecules leading to functional modulation or modification. Besides amylase's function in carbohydrate breakdown, amylase can delay proteolytic degradation of protein partners (e.g., histatin 1) when complexed. Due to its biochemical characteristics and high abundance in saliva, amylase probably interacts with several proteins acting as a biological carrier. This study focused on identifying interactions between amylase and other proteins found in whole saliva (WS) using proteomic approaches. Affinity chromatography was used, followed by gel electrophoresis methods, sodium dodecyl sulfate and native, tryptic in-solution and in-gel digestion, and mass spectrometry. We identified 66 proteins that interact with amylase in WS. Characterization of the identified proteins suggests that acidic (pI

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Novel Compliant Scaffold with Specific Design for Venous System: Results of a Porcine Model Study

Background. Stenting has become the first-line treatment of obstructive venous disease because of poor results of balloon angioplasty. This preclinical study aimed to investigate the safety and efficacy profile of a novel compliant venous scaffold (CVS) denominated Petalo CVS, specifically designed for venous diseases. Materials and Methods. Twelve healthy pigs weighing 90 kg were used to test Petalo CVS. The devices were implanted into the internal jugular veins (IJVs) using a femoral vein percutaneous approach. The safety profile including the success rate of device releasing, anchoring, and positioning was evaluated immediately. Fracture, migration, primary patency, and endothelial response were assessed at 1, 2, 3, and 6 months after the study procedure. Results. A total of 32 devices were successfully released in both IJVs. No procedure- or device-related complications were reported, and all pigs successfully completed the different scheduled follow-up periods. The primary patency rate was 100%, and no fracture or migration of the device into the brachiocephalic trunk was reported. Histological examination revealed only minimal lesions with minimal or absent inflammatory reaction surrounding the incorporated metallic rods. Conclusions. This porcine model study showed a promising safety and efficacy profile of Petalo CVS, a novel endovenous device based on specific concepts.

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Physician Awareness of Immune Responses to Polyethylene Glycol-Drug Conjugates

Abstract

Antibodies against polyethylene glycol (PEG) can critically jeopardize the efficacy and safety of PEGylated therapeutics. For some PEG-drugs, a sizeable fraction of patients develop anti-PEG antibodies (APA), leading to reduced efficacy and potential adverse events. We surveyed physicians from several specialties to assess their awareness of APA. Overall, 83% of the physicians surveyed indicated that they have recently prescribed PEGylated drugs. Although 91% of respondents were aware of antidrug antibodies in general, only 22% were aware of APA responses. Further, there was limited awareness (35%) of PEG's inclusion in prescribed PEGylated therapeutics. These findings bring to light a need for improved awareness of APA, potentially via targeted education of physicians who prescribe specific PEGylated therapeutics that could induce or are otherwise affected by APA. Finally, it will be critical to quantitate the extent of knowledge transfer from the research community to clinicians, especially on topics of patient safety.

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Co-circulation and simultaneous co-infection of dengue, chikungunya, and zika viruses in patients with febrile syndrome at the Colombian-Venezuelan border

In Colombia, the dengue virus (DENV) has been endemic for decades, and with the recent entry of the chikungunya virus (CHIKV) (2014) and the Zika virus (ZIKV) (2015), health systems are overloaded because the ...

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Bioinspired, Spine-Like, Flexible, Rechargeable Lithium-Ion Batteries with High Energy Density

Abstract

The rapid development of flexible and wearable electronics proposes the persistent requirements of high-performance flexible batteries. Much progress has been achieved recently, but how to obtain remarkable flexibility and high energy density simultaneously remains a great challenge. Here, a facile and scalable approach to fabricate spine-like flexible lithium-ion batteries is reported. A thick, rigid segment to store energy through winding the electrodes corresponds to the vertebra of animals, while a thin, unwound, and flexible part acts as marrow to interconnect all vertebra-like stacks together, providing excellent flexibility for the whole battery. As the volume of the rigid electrode part is significantly larger than the flexible interconnection, the energy density of such a flexible battery can be over 85% of that in conventional packing. A nonoptimized flexible cell with an energy density of 242 Wh L⁻¹ is demonstrated with packaging considered, which is 86.1% of a standard prismatic cell using the same components. The cell also successfully survives a harsh dynamic mechanical load test due to this rational bioinspired design. Mechanical simulation results uncover the underlying mechanism: the maximum strain in the reported design (≈0.08%) is markedly smaller than traditional stacked cells (≈1.1%). This new approach offers great promise for applications in flexible devices.

A spine-like lithium-ion battery, fabricated through a scalable and facile approach, demonstrates a stable cycle performance in different stress conditions, and high energy density compared to commercial batteries. It also presents a steady cycling under dynamic mechanical load testing. Simulation results uncover a much smaller strain tolerated for the design compared with that in a prismatic cell and a stacked pouch cell.

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Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF15

Abstract

Transarterial chemoembolization (TACE) is the standard treatment for unresectable hepatocellular carcinoma (HCC). Hypoxia-induced angiogenesis by TACE is linked to treatment failure; however, whether the chemotherapeutic damage of TACE to HCC could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy-damaged HCC cells on the neo-angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (GDF15) was significantly upregulated in HCC cells exposed to chemotherapeutic agents. GDF15 from chemotherapy-damaged HCC cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro-angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK, and NF-κB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy-damaged HCC cells-promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in TACE to HCC could promote tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects.

Chemotherapeutic damage to hepatocellular carcinoma promotes tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects.

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Effectiveness of modified hyper-CVAD chemotherapy regimen in the treatment of adult acute lymphoblastic leukemia: a retrospective experience

Abstract

Several chemotherapy regimens have been developed for the treatment of acute lymphoblastic leukemia (ALL), but relapse still presents the most common obstacles to attaining long-term survival. The hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and prednisolone)/HD MTX and Ara-C (high-dose methotrexate and cytarabine) chemotherapy regimen was first started in the MD Anderson Cancer Center as an intensive regimen for adult patients with ALL. The purpose of this study was to evaluate the effectiveness of a modified hyper-CVAD protocol. We used hyper-CVAD as consolidation/maintenance after remission induction with daunorubicin, vincristine, and prednisolone (and cyclophosphamide for T-cell ALL only) rather than standard hyper-CVAD in order to reduce treatment complications. This study was conducted as a retrospective review of medical records of ALL patients at 501 army hospital, Tehran, Iran, from 2005 to 2015. Three hundred and one patients underwent modified hyper-CVAD chemotherapy regimen. Complete remission and overall survival (OS) rates were measured as primary endpoints. Two hundred and forty-six (81.7%) reached complete remission (CR) during the first 6 months of treatment, and 55 patients (18.3%) did not reach CR. The 5-year OS rate was 51.8% (95% CI (confidence interval): 45.1–57.8%). Modified hyper-CVAD regimen is an efficient intensive chemotherapy regimen for consolidation/maintenance of adults with newly diagnosed ALL and has an acceptable 5-year overall that is comparable to standard hyper-CVAD regimen.

We used a modified hyper-CVAD protocol to reduce treatment-related mortality and simultaneously reach an acceptable overall survival in patients with adult ALL. The results were promising, and it seems that this protocol could be of great benefit for ALL patients.

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Novel applications for an established antimalarial drug: tumoricidal activity of quinacrine

Future Oncology, Ahead of Print.


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CPX-351: changing the landscape of treatment for patients with secondary acute myeloid leukemia

Future Oncology, Ahead of Print.


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The flavonoid hesperidin exerts anti-photoaging effect by downregulating matrix metalloproteinase (MMP)-9 expression via mitogen activated protein kinase (MAPK)-dependent signaling pathways

Hesperidin is a flavonoid with antioxidant, anti-inflammatory, and immune modulatory activities. Photoaging is a consequence of chronic exposure to the sun and ultraviolet (UV) radiation. This study was design...

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Screening of Baccaurea ramiflora (Lour.) extracts for cytotoxic, analgesic, anti-inflammatory, neuropharmacological and antidiarrheal activities

It has been observed that the various part of Baccaurea ramiflora plant is used in rheumatoid arthritis, cellulitis, abscesses, constipation and injuries. This plant also has anticholinergic, hypolipidemic, hypog...

http://ift.tt/2GzCQv0

Study on the inhibition of Mfn1 by plant-derived miR5338 mediating the treatment of BPH with rape bee pollen

Recent studies have found that plant derived microRNA can cross-kingdom regulate the expression of genes in humans and other mammals, thereby resisting diseases. Can exogenous miRNAs cross the blood-prostate b...

http://ift.tt/2rQmJG1

The frequency of missed breast cancers in women participating in a high-risk MRI screening program

Abstract

Purpose

To evaluate the frequency of missed cancers on breast MRI in women participating in a high-risk screening program.

Methods

Patient files from women who participated in an increased risk mammography and MRI screening program (2003–2014) were coupled to the Dutch National Cancer Registry. For each cancer detected, we determined whether an MRI scan was available (0–24 months before cancer detection), which was reported to be negative. These negative MRI scans were in consensus re-evaluated by two dedicated breast radiologists, with knowledge of the cancer location. Cancers were scored as invisible, minimal sign, or visible. Additionally, BI-RADS scores, background parenchymal enhancement, and image quality (IQ; perfect, sufficient, bad) were determined. Results were stratified by detection mode (mammography, MRI, interval cancers, or cancers in prophylactic mastectomies) and patient characteristics (presence of BRCA mutation, age, menopausal state).

Results

Negative prior MRI scans were available for 131 breast cancers. Overall 31% of cancers were visible at the initially negative MRI scan and 34% of cancers showed a minimal sign. The presence of a BRCA mutation strongly reduced the likelihood of visible findings in the last negative MRI (19 vs. 46%, P < 0.001). Less than perfect IQ increased the likelihood of visible findings and minimal signs in the negative MRI (P = 0.021).

Conclusion

This study shows that almost one-third of cancers detected in a high-risk screening program are already visible at the last negative MRI scan, and even more in women without BRCA mutations. Regular auditing and double reading for breast MRI screening is warranted.

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Reverse of non-small cell lung cancer drug resistance induced by cancer associated fibroblasts via a paracrine pathway

Abstract

Tumor microenvironment orchestrates the sustained growth, metastasis and recurrence of cancer. As an indispensable component of tumor microenvironment, cancer associated fibroblasts (CAFs) are considered as an essential synthetic machine producing various tumor components, leading to cancer sustained stemness, drug resistance and tumor recurrence. Here, we developed a sustainable primary culture of lung cancer cells fed with lung cancer associated fibroblasts, resulting in enrichment and acquisition of drug resistance in cancer cells. Moreover, IGF2/AKT/Sox2/ABCB1 signaling activation in cancer cells was observed in the presence of cancer associated fibroblasts, which induce P-glycoprotein (P-GP) up-regulated expression and the drug resistance of non-small cell lung cancer cells. Our results demonstrated that cancer associated fibroblast cells constitute a supporting niche for cancer drug resistance acquisition. Thus, traditional chemotherapy combined with IGF2 signaling inhibitor may present an innovative therapeutic strategy for non-small cell lung cancer therapy.

This article is protected by copyright. All rights reserved.

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lncRNA BC005927 upregulates EPHB4 and promotes gastric cancer metastasis under hypoxia

Summary

Hypoxia plays a critical role in the metastasis of gastric cancer (GC), yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs are involved in the contribution of hypoxia to the GC metastasis. In this study, we found that lncRNA BC005927 can be induced by hypoxia in GC cells and mediates hypoxia-induced GC cell metastasis. Furthermore, BC005927 is frequently up-regulated in GC samples and increased BC005927 expression was correlated with a higher tumor-node-metastasis stage. GC patients with higher BC005927 expression had poorer prognoses than those with lower expression. Additional experiments revealed that BC005927 expression is induced by HIF-1a, CHIP assay and luciferase reporter assays confirmed that this lncRNA is a direct transcriptional target of HIF-1a. Next, we found that EPHB4, a metastasis-related gene, is regulated by BC005927 and that the expression of EPHB4 was positively correlated with that of BC005927 in the clinical GC samples assessed. Intriguingly, EPHB4 expression was also increased under hypoxia, and its upregulation by BC005927 resulted in hypoxia-induced GC cell metastasis. These results advance the current understanding of the role of BC005927 in the regulation of hypoxia signaling and offer new avenues for the development of therapeutic interventions against cancer progression.

This article is protected by copyright. All rights reserved.

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First PARP Inhibitor Approved for Breast Cancer [News in Brief]

Olaparib also becomes the first targeted therapy for patients with germline BRCA mutations.

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Venetoclax Data Prompt Rethink of CLL Therapy [News in Depth]

BCL2 inhibitor yields deep remissions when used alone and in combinations.

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In Reply to Leddy

To the Editor: The authors appreciate the commenter's description (1) of a shift in fundraising strategy to increase the percentage of active, domestic American Society for Radiation Oncology (ASTRO) members who contribute to the ASTRO political action committee (PAC) from the current 4% who contribute.

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Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies

Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells. Therefore, evolutionary strategies should be used with conventional therapies to delay or prevent resistance. Using an agent-based framework to model spatial competition among sensitive and resistant populations, we applied anti-proliferative drug treatments to varying ratios of sensitive and resistant cells. We compared a continuous maximum tolerated dose schedule with an adaptive schedule aimed at tumor control via competition between sensitive and resistant cells. Continuous treatment cured mostly sensitive tumors, but with any resistant cells, recurrence was inevitable. We identified two adaptive strategies that control heterogeneous tumors: dose modulation controls most tumors with less drug, while a more vacation-oriented schedule can control more invasive tumors. These findings offer potential modifications to treatment regimens that may improve outcomes and reduce resistance and recurrence.

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Tumorigenic and anti-proliferative properties of the TALE-transcription factors MEIS2D and MEIS2A in neuroblastoma

Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify a MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.

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Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody-Drug Conjugates

AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADC have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCEC internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. We observed the same mechanism for target-independent internalization of AGS-16C3F in fibroblasts and human umbilical vein endothelial cells (HUVEC). Macropinocytosis-mediated intake of macromolecules is facilitated by the presence of positive charges or hydrophobic residues on the surface of the macromolecule. Modification of AGS-16C3F, either by attachment of poly-glutamate peptides, mutation of residue K16 to D on AGS-16C3F (AGS-16C3F(K16D)), or decreasing the overall hydrophobicity via attachment of polyethylene glycol moieties, significantly reduced cytotoxicity against HCEC and other primary cells. Rabbits treated with AGS-16C3F showed significant ocular toxicity, whereas those treated with AGS-16C3F(K16D) presented with less severe and delayed toxicities. Both molecules displayed similar anti-tumor activity in a mouse xenograft model. These findings establish a mechanism of action for target-independent toxicities of AGS-16C3F and ADCs in general, and provide methods to ameliorate these toxicities.

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HER2 overexpression triggers an IL-1{alpha} pro-inflammatory circuit to drive tumorigenesis and promote chemotherapy resistance

Systemic inflammation in breast cancer correlates with poor prognosis but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation and expansion of the mammary stem/progenitor and cancer stem-like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feed-forward activation loop of IL-1α and IL-6 that stimulated NF-κB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2-induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL-1α/IL-6 expression and CSC-positive phenotype. Pharmacologic blockade of IL-1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.

http://ift.tt/2E2sGEM

Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer.

The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.

http://ift.tt/2FvfWDL

Watch and Wait, Salvage Later

For this patient (1) with localized resected nodular lymphocyte predominant Hodgkin lymphoma, we favor a "watch and wait" approach or radiation therapy alone after a frank discussion of the pros and cons of each approach (2). Observation after complete resection in early-stage disease has been studied predominantly in the pediatric population, with 1 study showing an overall progression-free survival of 67% at 26 months (3). In adults there are little data of observation alone. In 1 study the addition of radiation therapy improved progression-free survival.

http://ift.tt/2ErlG1U

Observe, and Keep Chemotherapy Up the Sleeve

In this case of an adult with completely resected disease (1), the choices for therapy are observation or radiation therapy alone. Extrapolating from a pediatric population with residual disease per Children's Oncology Group study AHOD03P1, chemotherapy (adriamycin, vincristine, prednisone, and cyclophosphamide) would be supported because it confers an excellent 5-year event-free survival of 88.1% (2). Additionally, those patients with resected disease who were observed had a 5-year event-free survival of 77%.

http://ift.tt/2DOa1Je

In Reply to Overgaard et al

To the Editor: We appreciate Dr Overgaard's comments regarding our recent analysis of US fractionation patterns in early-stage glottic cancer (1, 2). He raises 2 intriguing points: first, whether the survival difference that we and others (3) have observed between fractionation schedules is plausible given highly effective surgical salvage; and second, whether the survival difference may be better explained by total duration of radiation therapy than by dose per fraction.

http://ift.tt/2EqGEhy

Dedicating “Empowering Intensity Modulated Proton Therapy Through Physics and Technology: An Overview” to the Memory of Dr Michael Goitein

To the Editor: We would like to dedicate our publication "Empowering Intensity Modulated Proton Therapy Through Physics and Technology: An Overview" (1) to the memory of Dr Michael Goitein (2) for the huge impact of his pioneering contributions on the evolution of the various concepts and technologies in the fields of radiation oncology and medical physics. Through his efforts during a period of four decades starting in the early 1970s, Dr Goitein laid the foundation for much of the progress and recent developments in these fields.

http://ift.tt/2DPhZCd

Meetings

March 2-4, 2018

http://ift.tt/2EomEvI

In Reply to Daisne et al

To the Editor: We would like to thank Daisne and colleagues for their letter regarding our article on the clinical outcomes of RapidArc versus Tomotherapy for patients with head and neck cancer (1).

http://ift.tt/2DQge7O

Stereotactic Radiosurgery for Resected Brain Metastases: New Evidence Supports a Practice Shift, but Questions Remain

Brain metastases are a common and devastating complication of cancer. Surgical resection of brain metastases remains an important treatment modality, especially for larger lesions with symptomatic mass effect. However, recurrence in the surgical bed occurs in approximately 60% of cases following resection alone (1, 2). For decades, the addition of postoperative adjuvant whole-brain radiation therapy (WBRT) has been the standard of care on the basis of randomized studies demonstrating efficacy in reducing the risk of recurrence in the surgical bed and the incidence of new metastases (1, 2).

http://ift.tt/2EsPyuU

Seymour H. Levitt, MD, 1928-2017

Dr Seymour H. Levitt died September 30, 2017, in Los Angeles, California, after a long illness.

http://ift.tt/2DLyvmx

Radiation Oncology in Egypt: A Model for Africa

Radiation therapy was first used in Egypt in the 1930s. Treatment was offered at the Kasr El Ainy Hospital (Cairo University Hospital) and delivered using the ominous sounding "Radium Bomb." This machine held 1 g of radium in an egg-shaped, lead-lined head, just inches from the tumor. A simple shutter was opened and closed by a bicycle break cable. The lead that lined the egg offered some direction to the beam and some protection to both healthy tissue and the treating staff. At that time, just as everywhere in the world, radiation oncology did not exist as a distinct specialty and, instead, was a part of the Department of Radiology, Tumor Management and Electrotherapy, at Cairo Faculty of Medicine.

http://ift.tt/2EsPo6M

In Regard to Bibault et al

To the Editor: We read with great interest the article "Clinical outcomes of several IMRT techniques for patients with head and neck cancer: A propensity score-weighted analysis" (1) and felt uncomfortable with some methodologic issues and the conclusion they support. First, the absence of randomization is a major drawback. Though a propensity score–weighted analysis was performed to minimize the biases of the patients population, it does not correct the potential biases linked to the physicians and the centers.

http://ift.tt/2DNTHbF

Contact Radiation Therapy for Achieving Organ Preservation in Rectal Cancer After Standard Neoadjuvant Chemoradiation: Looking for a Place in the Sun

The concept of organ preservation in rectal cancer is now less controversial than it used to be (1, 2). The benefits from avoiding radical proctectomy and its associated immediate morbidity and mortality, functional consequences, and requirement for stomas have been demonstrated in multiple series (3, 4). Coupled with the acceptable oncologic outcomes following no immediate surgery, patients with complete clinical response (including clinical, endoscopic, and radiological) are now offered or at least are made aware of this "Watch & Wait" strategy (5, 6).

http://ift.tt/2EplH6t

Issue Highlights

Minniti et al

http://ift.tt/2ErfmYb

In Reply to McClelland et al

To the Editor: We thank McClelland et al for their insightful comments on our study. We were also alarmed by the high stroke rate in our cohort (1). It is certainly possible that the treatment technique in our study contributed to the high stroke rate, including increased relative biological effectiveness at the distal end of the Bragg peak (2), less conformal dose distribution of older treatment delivery techniques, and perhaps other unappreciated biological differences between protons and photons.

http://ift.tt/2DPARAH

In Regard to Sanford et al

To the Editor: We read with interest Sanford et al's report (1) on their prospective study examining fractionated radiation therapy (RT) for residual/recurrent benign meningioma after resection; we applaud the authors for being the first to conduct such a study and for demonstrating the integrity and courage to present their complications wholeheartedly. Although the 98% 10-year and 90% 15-year local control rates are impressive, we were particularly alarmed at the more than 20% stroke rate at the authors' median 17-year follow up (along with the near 60% rate of grade 2+ toxicity).

http://ift.tt/2EoQ8JR

B Cell Receptor and CD40 Signaling Are Rewired for Synergistic Induction of the c-Myc Transcription Factor in Germinal Center B Cells

Luo et al. show that CD40 and BCR signaling in GC B cells is rewired to control very different pathways, and both signals are required for optimal induction of c-Myc, suggesting a mechanism of signaling-directed positive selection of GC B cells.

http://ift.tt/2nvoMts

Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR4

Glucocorticoids have strong immunosuppressive effects, yet their physiological functions in the immune system remain unclear. Shimba et al. demonstrate that glucocorticoids drive IL-7R expression in a diurnal fashion, which induces the redistribution of T cells between peripheral blood and lymphoid organs via CXCR4 expression and enhances adaptive immune responses.

http://ift.tt/2DSc82Y

Chromatin Configuration Affects the Dynamics and Distribution of a Transiently Interacting Protein

We present a theoretical study of the interaction between a protein (diffusing particle) and chromatin (polymer chain). Each monomer is a trap where a particle can transiently bind. We derive, to our knowledge, novel formulas for the transition rate between monomer sites, given a specific polymer configuration, and find that a particle is likely to rapidly rebind many times to its release site before moving to another site. The reattachment probability is larger when the local density around the release site is smaller.

http://ift.tt/2DMpnht

Structural Conservation and Effects of Alterations in T Cell Receptor Transmembrane Interfaces

T cell receptors (TCRs) are octameric assemblies of type-I membrane proteins in which a receptor heterodimer (αβ, δγ, or pre-Tαβ) is associated with three dimeric signaling modules (CD3δε, CD3γε, and ζζ) at the T cell or pre-T cell surface. In the human αβTCR, the α and β transmembrane (TM) domains form a specific structure that acts as a hub for assembly with the signaling modules inside the lipid bilayer. Conservation of key polar contacts across the C-terminal half of this TM interface suggests that the structure is a common feature of all TCR types.

http://ift.tt/2EoL748

Effect of Grafting on Aggregation of Intrinsically Disordered Proteins

A significant part of the proteome is composed of intrinsically disordered proteins (IDPs). These proteins do not fold into a well-defined structure and behave like ordinary polymers. In this work, we consider IDPs that have the tendency to aggregate, model them as heteropolymers that contain a small number of associating monomers, and use computer simulations to compare the aggregation of such IDPs that are grafted to a surface or free in solution. We then discuss how such grafting may affect the analysis of in vitro experiments and could also be used to suppress harmful aggregation.

http://ift.tt/2DQGz5i

Lateral cervical thymic cyst in a child: a case report

Cervical thymic cysts are uncommon lesions, rarely considered in the differential diagnosis of neck cysts in children.

http://ift.tt/2E0F3AV

Skilled delivery service utilization and its association with the establishment of Women’s Health Development Army in Yeky district, South West Ethiopia: a multilevel analysis

Because of the unacceptably high maternal and perinatal morbidity and mortality, the government of Ethiopia has established health extension program with a community-based network involving health extension wo...

http://ift.tt/2Fv690t

Higher cut-off serum procalcitonin level for sepsis diagnosis in metastatic solid tumor patients

The current study aimed to know procalcitonin levels in patients with metastatic tumor, and to discover the cut-off point for sepsis in this population. A cross-sectional study was conducted with patients with...

http://ift.tt/2E3josc

External validation of risk prediction models for incident colorectal cancer using UK Biobank

External validation of risk prediction models for incident colorectal cancer using UK Biobank

External validation of risk prediction models for incident colorectal cancer using UK Biobank, Published online: 30 January 2018; doi:10.1038/bjc.2017.463

External validation of risk prediction models for incident colorectal cancer using UK Biobank

http://ift.tt/2BGnnFC

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07), Published online: 30 January 2018; doi:10.1038/bjc.2017.465

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

http://ift.tt/2noS2mv

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer, Published online: 30 January 2018; doi:10.1038/bjc.2017.474

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

http://ift.tt/2noY6eO

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages, Published online: 30 January 2018; doi:10.1038/bjc.2017.451

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

http://ift.tt/2BF7lfd

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer, Published online: 30 January 2018; doi:10.1038/bjc.2017.472

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

http://ift.tt/2nmIkRx

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study, Published online: 30 January 2018; doi:10.1038/bjc.2017.462

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

http://ift.tt/2nmIiZV

Indeterminate nodules in osteosarcoma: what’s the follow-up?

Indeterminate nodules in osteosarcoma: what's the follow-up?

Indeterminate nodules in osteosarcoma: what's the follow-up?, Published online: 30 January 2018; doi:10.1038/bjc.2017.453

Indeterminate nodules in osteosarcoma: what's the follow-up?

http://ift.tt/2BEquOs

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors, Published online: 30 January 2018; doi:10.1038/bjc.2017.476

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

http://ift.tt/2BFqqhg

Effects and Mechanisms of Tastants on the Gustatory-Salivary Reflex in Human Minor Salivary Glands

The effects and mechanisms of tastes on labial minor salivary gland (LMSG) secretion were investigated in 59 healthy individuals. Stimulation with each of the five basic tastes (i.e., sweet, salty, sour, bitter, and umami) onto the tongue induced LMSG secretion in a dose-dependent manner. Umami and sour tastes evoked greater secretion than did the other tastes. A synergistic effect of umami on LMSG secretion was recognized: a much greater increase in secretion was observed by a mixed solution of monosodium glutamate and inosine 5′-monophosphate than by each separate stimulation. Blood flow (BF) in the nearby labial mucosa also increased following stimulation by each taste except bitter. The BF change and LMSG secretion in each participant showed a significant positive correlation with all tastes, including bitter. Administration of cevimeline hydrochloride hydrate to the labial mucosa evoked a significant increase in both LMSG secretion and BF, while adrenaline, atropine, and pirenzepine decreased LMSG secretion and BF. The change in LMSG secretion and BF induced by each autonomic agent was significantly correlated in each participant. These results indicate that basic tastes can induce the gustatory-salivary reflex in human LMSGs and that parasympathetic regulation is involved in this mechanism.

http://ift.tt/2nrMAi1

Demystifying MR Neurography of the Lumbosacral Plexus: From Protocols to Pathologies

Magnetic resonance neurography is a high-resolution imaging technique that allows evaluating different neurological pathologies in correlation to clinical and the electrophysiological data. The aim of this article is to present a review on the anatomy of the lumbosacral plexus nerves, along with imaging protocols, interpretation pitfalls, and most common pathologies that should be recognized by the radiologist: traumatic, iatrogenic, entrapment, tumoral, infectious, and inflammatory conditions. An extensive series of clinical and imaging cases is presented to illustrate key-points throughout the article.

http://ift.tt/2DPx3Uh

Ticagrelor attenuates myocardial ischemia-reperfusion injury possibly through downregulating galectin-3 expression in the infarct area of rats

Abstract

Aims

The full benefits of myocardial revascularization strategies applied to acute myocardial infarction patients might be reduced by myocardial ischemia and reperfusion (I/R) injury. It is known that inflammation plays an important role in the pathogenesis of I/R injury and galectin-3, a known inflammatory factor, is actively involved in ischemia-induced inflammation and fibrosis of various organs. Previous studies demonstrated that anti-platelets therapy with ticagrelor, a new P2Y12 receptor antagonist, could effectively attenuate myocardial I/R injury and I/R injury related inflammatory responses. It remains unknown whether the cardioprotective effects of ticagrelor are also mediated by modulating myocardial galectin-3 expression.

Methods

We determined the ratio of infarct area (IA)/area at risk (AAR), expression of galectin-3, TNF-α and IL-6 in infarct area of placebo (equal volume saline per gastric gavage immediately after LAD ligation, then once daily till study end) or ticagrelor (150mg/kg dissolved in saline per gastric gavage immediately after LAD ligation, then once daily till study end) treated rats at 24h, 3 and 7 days post I (45min)/R injury. Sham operated rats served as control.

Results

Our results showed that ticagrelor treatment significantly reduced IA/AAR ratio at 3 and 7 days post I/R, downregulated mRNA and protein expression of galectin-3, as well as mRNA expression of TNF-α and IL-6 in infarct area at 24h, 3 and 7 days post I/R.

Conclusions

Our results thus suggest that the cardioprotective effects of ticagrelor might partly be mediated by downregulating galectin-3 expression in infarct area in this rat model of myocardial I/R injury.

http://ift.tt/2DJjBgv

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

http://ift.tt/2EqueGl

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

http://ift.tt/2DMBFGC

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

http://ift.tt/2Eque9j

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

http://ift.tt/2DMAIhn

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

http://ift.tt/2Eocco4

Indeterminate nodules in osteosarcoma: what’s the follow-up?

http://ift.tt/2FvzAPI

External validation of risk prediction models for incident colorectal cancer using UK Biobank

http://ift.tt/2E1psB6

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

http://ift.tt/2FvaIYA

Synthesizing Sodium Tungstate and Sodium Molybdate Microcapsules via Bacterial Mineral Excretion

This work presents a protocol for manufacture sodium tungstate and sodium molybdate microcapsules via bacteria and their corresponding nanoparticles.

http://ift.tt/2DROrI4

A Co-culture Method to Investigate the Crosstalk Between X-ray Irradiated Caco-2 Cells and PBMC

We present a protocol to investigate the crosstalk between X-ray-irradiated Caco-2 and peripheral blood mononuclear cells (PBMC). The protocol starts with Caco-2 irradiation and set-up of the co-culture with PBMC; subsequently, trans-epithelial electrical resistance is measured regularly over 48 h and western blot performed in both Caco-2 and PBMC.

http://ift.tt/2rRjn5x

The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib

Summary

Aims

We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor kinase inhibitor osimertinib, in patients with advanced non-small cell lung cancer in two phase I, open-label, two-part clinical studies. Part one of both studies is reported.

Methods

In the itraconazole study (NCT02157883), patients received single-dose osimertinib 80 mg on Days 1 and 10 and itraconazole (200 mg twice daily) on Days 6–18 orally. In the rifampicin study (NCT02197247), patients received osimertinib 80 mg once daily on Days 1–77 and rifampicin 600 mg once daily on Days 29–49.

Results

In the itraconazole study (n=36), the geometric least squares mean (GMLSM) ratios (osimertinib plus itraconazole/osimertinib alone) for C_max and AUC were 80% (90% CI 73, 87) and 124% (90% CI 115, 135), respectively; below the predefined no-effect upper limit of 200%. In the rifampicin study (n=40), the GMLSM ratios (osimertinib plus rifampicin/osimertinib alone) for C_ss,max and AUC_T were 27% (90% CI 24, 30%) and 22% (90% CI 20, 24%), respectively; below the predefined no-effect lower limit of 50%. The induction effect of rifampicin was apparent within 7 days of initiation; osimertinib C_ss,max and AUC_T values returned to pre-rifampicin levels within 3 weeks of rifampicin discontinuation. No new osimertinib safety findings were observed.

Conclusions

Osimertinib can be co-administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible.

http://ift.tt/2DY6wDn

TARGET Study Finds Major Differences between Childhood and Adult AML

An NCI-funded study has found significant differences in the genetics of acute myeloid leukemia in younger and older patients. The findings could help guide the development of treatments tailored specifically for childhood AML.

http://ift.tt/2EqGyXc

Using Three-color Single-molecule FRET to Study the Correlation of Protein Interactions

Here, we present a protocol to obtain three-color smFRET data and its analysis with a 3D ensemble Hidden Markov Model. With this approach, scientists can extract kinetic information from complex protein systems, including cooperativity or correlated interactions.

http://ift.tt/2EnPX1w

Cystometric and External Urethral Sphincter Measurements in Awake Rats with Implanted Catheter and Electrodes Allowing for Repeated Measurements

This protocol first describes the surgical procedure of the permanent implantation of a urinary bladder catheter combined with external urethral sphincter electrodes, and second, the measurement of the function of the urinary bladder and external urethral sphincter in implanted awake animals.

http://ift.tt/2DOok0q

Tumor progression locus 2 in hepatocytes potentiates both liver and systemic metabolic disorders

Abstract

Tumor progression locus 2 (TPL2), a serine/threonine kinase, has been regarded as a potentially interesting target for the treatment of various diseases with an inflammatory component. However, the function of TPL2 in regulating hepatocyte metabolism and liver inflammation during the progression of non-alcoholic fatty liver disease (NAFLD) is poorly understood. Here, we report that TPL2 protein expression was significantly increased in fatty liver from diverse species, including humans, monkeys and mice. Further investigations revealed that compared to wild-type littermates, hepatocyte-specific TPL2 knockout mice exhibited improved lipid and glucose imbalance, reserved insulin sensitivity and alleviated inflammation in response to high-fat diet (HFD) feeding. Overexpression of TPL2 in hepatocytes led to the opposite phenotype. Regarding the mechanism, we found that MKK7 was the specific substrate of TPL2 for JNK activation. TPL2-MKK7-JNK signaling in hepatocytes represents a promising drugable target for treating NAFLD and associated metabolic disorders.

Conclusions: In hepatocytes, TPL2 acts as a key mediator that promotes both liver and systemic metabolic disturbances by specifically increasing MKK7-JNK activation. This article is protected by copyright. All rights reserved.

http://ift.tt/2rUPvFz

Investigation of an antitumor drug-delivery system based on anti-HER2 antibody-conjugated BSA nanoparticles

Conjugation of a monoclonal antibody with a nanoparticle often improves its specificity and drug loading in cancer therapy. In this study, we prepared a novel targeting nanodrug-delivery system using 2-methoxy-estradiol (2-ME) based on anti-human epidermal growth factor receptor 2 (HER2) antibody-modified BSA to improve the clinical application and antitumor effect of 2-ME. 2-ME-loaded albumin nanoparticles (2-ME-BSANPs) were prepared using a desolvation method and the anti-HER2 antibodies were conjugated to 2-ME-BSANPs (HER2-2-ME-BSANPs) using the coupling agent, succinimidyl 3-(2-pyridyldithio)propionate. HER2-2-ME-BSANPs were characterized using SDS-polyacrylamide gel electrophoresis, an agglutination test, and an immunofluorescence assay. We found that mouse anti-human anti-HER2 monoclonal antibody was successfully conjugated to the 2-ME-BSANPs. Thereafter, the in-vitro and in-vivo toxicities were evaluated using two cancer cell lines, SK-BR-3 (HER2-overexpressing) and MCF-7 (HER2-underexpressing), using classic pharmacological methods and in-vivo imaging technology. We found that the HER2-2-ME-BSANPs retained the immunospecificity of the anti-HER2 monoclonal antibody, rapidly localized to HER2 receptors, and could be used for targeted cancer therapy. Correspondence to Dr Qingfeng Tian, College of Public Health, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China Tel/fax: +86 371 6778 1393; e-mail: 13937156869@126.com Received August 23, 2017 Accepted December 5, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2DNwpqh

Comparison of the effect of the antiandrogen apalutamide (ARN-509) versus bicalutamide on the androgen receptor pathway in prostate cancer cell lines

Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide. We compared the activity of ARN versus bicalutamide on prostate cancer cell lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, as well as the levels of the AR downstream proteins prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or hypoxia. The effects on autophagic flux (LC3A, p62, TFEB, LAMP2a, cathepsin D) and cell metabolism-related enzymes (hypoxia-inducible factor 1α/2α, BNIP3, carbonic anhydrase 9, LDHA, PDH, PDH-kinase) were also studied. The 22Rv1 cell line responded to testosterone by increasing the nuclear entry of AR, AR-V7, and phosphorylated AR and by increasing the levels of prostate-specific antigen and TMPRSS2. This effect was strongly abrogated by ARN and to a clearly lower extent by bicalutamide at 10 μmol/l, both in normoxia and in hypoxia. ARN had a stronger antiproliferative effect than bicalutamide, which was prominent in the 22Rv1 hormone-responsive cell line, and completely repressed cell proliferation at a concentration of 100 μmol/l. No effect of testosterone or of antiandrogens on autophagy flux, hypoxia-related proteins, or metabolism enzyme levels was noted. The PC3 and DU145 cell lines showed poor expression of the proteins and were not responsive to testosterone. On the basis of in-vitro studies, evidence has been reported that ARN is more potent than bicalutamide in blocking the AR pathway in normoxia and in hypoxia. This reflects a more robust, dose-dependent, repressive effect on cell proliferation. Correspondence to Michael I. Koukourakis, MD, Department of Radiotherapy/Oncology, Democritus University of Thrace, PO Box 12, Alexandroupolis 68100, Greece Tel: +30 255 107 4622; fax: 30 255 103 0349; e-mail: targ@her.forthnet.gr Received September 17, 2017 Accepted December 20, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2nqfj6O

Oscillatory activity in the cortico-basal ganglia-thalamic neural circuits in Parkinson's disease

Abstract

Dopamine is an important neurotransmitter that maintains the balance within the basal ganglia between the direct pathway, which promotes movement, and the indirect pathway, which inhibits movement. Degeneration of dopaminergic neurons in the substantia nigra increases the influence of the indirect pathway, resulting in motor dysfunction in Parkinson's disease (PD). The direct and indirect pathways are composed of cortical areas, basal ganglia, and thalamic nuclei, which are interconnected via independent parallel loop circuits and often referred to as cortico-basal ganglia-thalamic (CBT) neural circuits. CBT circuits have been useful in generating hypotheses to describe slowness in PD. Recent work has focused on aberrant neural oscillations within CBT circuits. Although beta (13-30 Hz) oscillations are a common feature of the CBT network, there is growing evidence that abnormally exaggerated beta oscillations, observed after dopamine loss in the CBT circuits, may contribute to motor symptoms of PD. Disruption of abnormal beta oscillations has been associated with the improvement of motor functions during pharmacological treatments, surgical lesions, and electrical stimulation. However, it is not clear how abnormal oscillations originate in the CBT motor network and resonate specifically in the beta band after the loss of dopamine. Most studies have addressed these questions by simultaneous recordings of oscillations in the motor cortex, basal ganglia nuclei, and motor regions of the thalamus in animal models of parkinsonism as well as in PD patients. This review further discusses previous and current studies of the changes in oscillatory activity at the level of CBT neural network in PD.

This article is protected by copyright. All rights reserved.

http://ift.tt/2rQvpMq

Behavioral Signatures of Backward Planning in Animals

Abstract

Goal-directed planning in behavioral and neural sciences is theorized to involve a prospective mental simulation that, starting from the animal's current state in the environment, expands a decision tree in a forward fashion. Backward planning in the artificial intelligence literature, however, suggests that agents expand a mental tree in a backward fashion starting from a certain goal state they have in mind. Here we show that several behavioral patterns observed in animals and humans, namely outcome-specific Pavlovian-to-instrumental transfer and differential-outcome effect, can be parsimoniously explained by backward planning. Our basic assumption is that the presentation of a cue that has been associated with a certain outcome triggers backward planning from that outcome state. On the basis of evidence pointing to forward and backward planning models, we discuss the possibility of brain using a bidirectional planning mechanism where forward and backward trees are expanded in parallel to achieve higher efficiency.

This article is protected by copyright. All rights reserved.

http://ift.tt/2GtDOZs

The Role of Alpha Oscillations in Distractor Inhibition during Memory Retention

Abstract

Only small amounts of visual information, as determined by the capacity of working memory, can be held in an active and accessible state. Thus, it is important to select and maintain information that is relevant while ignoring irrelevant information. However, the underlying neural mechanism of these processes has yet to be identified. One potential candidate are alpha oscillations (8–14 Hz), which have been shown to inhibit stimulus processing in perceptual tasks. During memory maintenance, alpha power increases with set size suggesting that alpha oscillations are involved either in memory maintenance or in the inhibition of task-irrelevant information in order to protect relevant information from interference. The need for such a protection should increase with the amount of distracting information, but most previous studies did not show any distractors. Therefore, we directly tested whether alpha oscillations are involved in inhibition of distractors during memory maintenance. Participants memorized the orientation of one or two target lines embedded among irrelevant distractors. Distractors were either strong or weak and were present during the retention interval after which participants reported the orientation of probed targets. Computational modelling showed that performance decreased with increasing set size and stronger distraction. Alpha power in the retention interval generally increased with set size, replicating previous studies. However, here stronger distractors reduced alpha power. This finding is in clear contradistinction to previous suggestions, as alpha power decrease indicates higher neuronal excitability. Thus, our data do not support the suggested role of alpha oscillations in inhibition of distraction in working memory.

This article is protected by copyright. All rights reserved.

http://ift.tt/2rQvfVk

Imodium (loperamide) for Over-the-Counter Use: Drug Safety Communication - FDA Limits Packaging To Encourage Safe Use

Audience: Consumer, Pharmacy, Family Practice [Posted 01/30/2018] ISSUE: To foster safe use of the over-the counter (OTC) anti-diarrhea drug loperamide, FDA is working with manufacturers to use blister packs or other single dose packaging and to...

http://ift.tt/2EpFNxv

Helicobacter pylori eradication treatment and the risk of gastric adenocarcinoma in a Western population

Objective

Gastric infection with Helicobacter pylori is a strong risk factor for non-cardia gastric adenocarcinoma. The aim of this study was to assess whether the risk of gastric adenocarcinoma and non-cardia gastric adenocarcinoma decreases after eradication treatment for H. pylori in a Western population.

Design

This was a nationwide, population-based cohort study in Sweden in 2005–2012. Data from the Swedish Prescribed Drug Registry provided information on H. pylori eradication treatment, whereas information concerning newly developed gastric adenocarcinoma was retrieved from the Swedish Cancer Registry. The risk of gastric adenocarcinoma and non-cardia gastric adenocarcinoma in individuals who had received H. pylori eradication treatment was compared with the background population of the corresponding age, sex and calendar year distribution, yielding standardised incidence ratios (SIRs) with 95% CIs.

Results

During the follow-up of 95 176 individuals who had received eradication treatment (351 018 person-years at risk), 75 (0.1%) developed gastric adenocarcinoma and 69 (0.1%) developed non-cardia gastric adenocarcinoma. The risk of gastric adenocarcinoma decreased over time after eradication treatment to levels below that of the corresponding background population. The SIRs were 8.65 (95% CI 6.37 to 11.46) for 1–3 years, 2.02 (95% CI 1.25 to 3.09) for 3–5 years and 0.31 (95% CI 0.11 to 0.67) for 5–7.5 years after eradication treatment. When restricted to non-cardia adenocarcinoma, the corresponding SIRs were 10.74 (95% CI 7.77 to 14.46), 2.67 (95% CI 1.63 to 4.13) and 0.43 (95% CI 0.16 to 0.93).

Conclusion

Eradication treatment for H. pylori seems to counteract the development of gastric adenocarcinoma and non-cardia gastric adenocarcinoma in this Western population.

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Potential of butyrate to influence food intake in mice and men

In recent years, many studies have been dedicated towards elucidating the role of the intestinal microbiota in metabolic health. It was suggested that specific intestinal microbial compositions can either protect from—or contribute to obesity and metabolic diseases. A causal relation between the microbiota and host metabolic profile was demonstrated when faecal microbiota of lean and obese subjects was transferred into mice, which then exhibited corresponding phenotypes.1 Short chain fatty acids (SCFAs) have broadly been proposed as key mediators in the microbiota-induced metabolic effects on the host. They are produced by bacterial fermentation of otherwise indigestible nutrients. The most abundant SCFAs are propionate, acetate and butyrate. All have been extensively studied in murine models for their possible influence on colonic health, glucose and lipid metabolism, as well as appetite and energy expenditure. Although various mechanisms by which these SCFAs exert their effect were suggested,2–7

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Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes

Objective

Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear.

Design

A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients.

Results

Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; P_multivariate<0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; P_multivariate=0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAF^wt/KRAS^wt, pMMR/BRAF^mut/KRAS^wt, pMMR/BRAF^wt/KRAS^mut) and transcriptomic (CMS 1-4) subtypes.

Conclusion

TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.

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Methods for Analyzing the Impacts of Natural Uranium on In Vitro Osteoclastogenesis

Uranium is known to affect bone metabolism. Here, we present a protocol aimed at investigating the effect of natural uranium exposure on the viability, the differentiation, and the function of osteoclasts, the cells in charge of bone resorption.

http://ift.tt/2rSgkKu

Detecting Behavioral Deficits in Rats After Traumatic Brain Injury

The goal of the behavioral tests presented here is to detect functional deficits in rats after traumatic brain injury. Four specific tests are presented that detect deficits in behaviors to reflect the damage to specific brain areas at times extending to one year after injury.

http://ift.tt/2GsRpAm

Imodium (loperamide) for Over-the-Counter Use: Drug Safety Communication - FDA Limits Packaging To Encourage Safe Use

Audience: Consumer, Pharmacy, Family Practice [Posted 01/30/2018] ISSUE: To foster safe use of the over-the counter (OTC) anti-diarrhea drug loperamide, FDA is working with manufacturers to use blister packs or other single dose packaging and to...

http://ift.tt/2EpFNxv

Targeting Pin1 by inhibitor API-1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, but there are few effective treatments. Aberrant microRNA (miRNA) biogenesis is correlated with HCC development. We previously demonstrated that prolyl isomerase Pin1 participates in miRNA biogenesis and is a potential HCC treatment target. However, how Pin1 modulates miRNA biogenesis remains obscure. Here, we present in vivo evidence that Pin1 overexpression is directly linked to the development of HCC. Administration with Pin1 inhibitor API-1, a novel and specific small molecule targeting Pin1 PPIase domain and inhibiting Pin1 cis-trans isomerizing activity, suppresses in vitro cell proliferation and migration of HCC cells. But API-1-induced Pin1 inhibition is insensitive to HCC cells with low Pin1 expression and/or low XPO5 phosphorylation. Mechanistically, Pin1 recognizes and isomerizes the phosphorylated Serine-Proline (pS-P) motif of pXPO5 and passivates pXPO5. Pin1 inhibition by API-1 maintains the active conformation of pXPO5, restores XPO5-driven precursor miRNA nuclear-to-cytoplasm export, activating anticancer miRNA biogenesis, and leading to both in vitro HCC suppression and HCC suppression in xenograft mice. Conclusion: Experimental evidence suggests Pin1 inhibition by API-1 upregulates miRNA biogenesis via retaining active XPO5 conformation and suppresses HCC development, revealing the mechanism of Pin1-mediated miRNA biogenesis and unequivocally supports API-1 as a novel drug candidate for HCC therapy, especially for Pin1-overexpressing, ERK-activated HCC. This article is protected by copyright. All rights reserved.

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PPPIs, Enterococcus and the Liver, Oh My!

http://ift.tt/2rMzFwo

Less can be more – a finite treatment approach for HBeAg-negative chronic hepatitis B

http://ift.tt/2GvqjbW

Implications of inter-correlation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: a case study with repaglinide

Summary

Aims

Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolising enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 inter-correlation on the predicted inter-individual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically-based pharmacokinetic (PBPK) modelling.

Methods

PBPK modelling and simulation was employed using Simcyp Simulator (v15.1). Virtual populations were generated assuming inter-correlations between hepatic CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers. A repaglinide PBPK model was used to predict pharmacokinetic parameters in presence and absence of gemfibrozil in virtual populations, and the results were compared with a clinical DDI study.

Results

Coefficient of variation (CV) of oral clearance was 52.5% in the absence of inter-correlation between CYP3A4-CYP2C8 abundances which increased to 54.2% when incorporating inter-correlation. In contrast, CV for predicted DDI (as measured by AUC ratio before and after inhibition) was reduced from 46.0% in the absence of inter-correlation between enzymes to 43.8% when incorporating inter-correlation: these CVs were associated with 5^th/95^th percentiles (2.48−11.29 vs. 2.49−9.69). The range of predicted DDI was larger in the absence of inter-correlation (1.55−77.06) than when incorporating inter-correlation (1.79−25.15), which was closer to clinical observations (2.6−12).

Conclusions

The present study demonstrates via a systematic investigation that population-based PBPK modelling incorporating inter-correlation led to more consistent estimation of extreme values with those observed in inter-individual variabilities of clearance and DDI. As the inter-correlations more realistically reflect enzyme abundances, virtual population studies involving PBPK and DDI should avoid using Monte Carlo assignment of enzyme abundance.

http://ift.tt/2rPrXBZ

Ubiquitin C decrement plays a pivotal role in replicative senescence of bone marrow mesenchymal stromal cells

Ubiquitin C decrement plays a pivotal role in replicative senescence of bone marrow mesenchymal stromal cells

Ubiquitin C decrement plays a pivotal role in replicative senescence of bone marrow mesenchymal stromal cells, Published online: 30 January 2018; doi:10.1038/s41419-017-0032-5

Ubiquitin C decrement plays a pivotal role in replicative senescence of bone marrow mesenchymal stromal cells

http://ift.tt/2BFLeFr

Where does O6-methylguanine DNA methyltransferase promoter methylation assessment place temozolomide in the future standards of care for glioblastoma?

Methylation of the promoter region of the O⁶-methylguanine DNA methyltransferase (MGMT) gene has emerged as the first—and so far the only—predictive biomarker for glioblastoma. Challenges in establishing a reliable assay to interrogate MGMT promoter methylation status and the lack of therapeutic alternatives to alkylating agent chemotherapy remain hurdles in the global implementation of MGMT testing as part of the standard of care.

http://ift.tt/2DOAtqj

Cancers, Vol. 10, Pages 39: Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer

Cancers, Vol. 10, Pages 39: Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer

Cancers doi: 10.3390/cancers10020039

Authors: Jiajia Zhang Christopher Wolfgang Lei Zheng

Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival. Despite the fact that immunotherapy with checkpoint blockade (e.g., anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] and anti-programmed cell death 1 [PD-1]/PD-L1 antibodies) has shown remarkable and durable responses in various cancer types, the application of checkpoint inhibitors in pancreatic cancer has been disappointing so far. It may, in part, due to the unique tumor microenvironment (TME) of pancreatic cancer, such as existence of excessive stromal matrix and hypovascularity, creating a TME of strong inhibitory signaling circuits and tremendous physical barriers for immune agent infiltration. This informs on the need for combination therapy approaches to engender a potent immune response that can translate to clinical benefits. On the other hand, lack of effective and validated biomarkers to stratify subgroup of patients who can benefit from immunotherapy poses further challenges for the realization of precision immune-oncology. Future studies addressing issues such as TME modulation, biomarker identification and therapeutic combination are warranted. In this review, advances in immunotherapy for pancreatic cancer were discussed and opportunities as well as challenges for personalized immune-oncology were addressed.

http://ift.tt/2rOP7IB

Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer

BACKGROUND

Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer.

METHODS

Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses.

RESULTS

The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance).

CONCLUSIONS

Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2rRL9Pt

Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE

BACKGROUND

Inotuzumab ozogamicin (InO) has demonstrated efficacy and tolerability in patients aged 18 to 78 years with relapsed/refractory acute lymphoblastic leukemia (ALL) in the INO-VATE trial. This subset analysis compared the efficacy and safety of InO in younger and older patients.

METHODS

Intent-to-treat analyses of morphologic responses and overall survival (OS) included 326 randomized patients, and safety assessments included 307 patients receiving 1 or more doses of the study treatment. Of the 326 patients, 164 received InO at a starting dose of 1.8 mg/m²/cycle (0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15 of a 21- to 28-day cycle [≤6 cycles]); 60 patients were aged ≥55 years, and 104 were aged <55 years.

RESULTS

For older and younger patients, the median duration of InO therapy and the types and frequencies of adverse events of any grade were generally similar. Although the remission rates, median duration of remission (DOR), and progression-free survival were similar with InO for those aged <55 years and those aged ≥55 years, OS was longer for younger patients (median, 8.6 vs 5.6 months; hazard ratio, 0.610). Among patients proceeding to hematopoietic stem cell transplantation after InO treatment (28% of older patients and 58% of younger patients), the incidence of veno-occlusive disease was greater in older patients (41% vs 17%). The study database was not locked at the time of this analysis.

CONCLUSIONS

InO was tolerable in older patients with relapsed/refractory ALL. Although OS was longer for younger patients versus older patients, InO demonstrated high response rates with similar DOR in the 2 age groups. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2GsBYZ3

A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy

Abstract

Members of the AAA+ superfamily of ATPases are involved in the unfolding of proteins and disassembly of protein complexes and aggregates. ATAD1 encoding the ATPase family, AAA+ domain containing 1-protein Thorase plays an important role in the function and integrity of mitochondria and peroxisomes. Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2. Using whole-exome sequencing, we identified a homozygous frameshift mutation in the last exon of ATAD1 [c.1070_1071delAT; p.(His357Argfs*15)] in three siblings who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes. Atad1−/− neurons expressing Thorase mutant^{His357Argfs*15} display reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane. Taken together, our molecular and functional analyses identify an activating ATAD1 mutation as a new cause of severe encephalopathy and congenital stiffness.

http://ift.tt/2njP8zB

An 8-Year-Old Child with Delayed Diagnosis of Netherton Syndrome

We report an 8-year-old boy with Netherton syndrome who was misdiagnosed and treated as severe atopic dermatitis. The diagnosis of Netherton syndrome was not made until the child was 8 years of age. We discuss the pitfalls in the diagnosis and alert physicians to the proper and early diagnosis of this syndrome. The child was treated with a low dose (0.25 mg/kg) of oral acitretin and a topical moisturizer with marked improvement of his skin and pruritus in 2 months. At 6-month follow-up, the skin was almost clear of erythema and scaling, and the hair was longer and stronger. The dose of acitretin was reduced to 0.12 mg/kg for another 6 months and then discontinued.

http://ift.tt/2DPyv9n

Balancing early access with uncertainties in evidence for drugs authorized by prospective case series – systematic review of reimbursement decisions

Summary

Aims

To review clinical and cost-effectiveness evidence underlying reimbursement decisions relating to drugs whose authorization mainly is based on evidence from prospective case series.

Methods

A systematic review of all new drugs evaluated in 2011–2016 within a health care profession-driven resource prioritization process, with a market approval based on prospective case series, and a reimbursement decision by the Swedish Dental and Pharmaceutical Benefits Board (TLV). Public assessment reports (EPARs) from the European Medicines Agency (EMA), published pivotal studies, and TLV, Scottish Medicines Consortium (SMC) and National Institute of Health and Care Excellence (NICE) decisions and guidance documents were reviewed.

Results

Six drug cases were assessed (brentuximab vedotin, bosutinib, ponatinib, idelalisib, vismodegib, ceritinib). The validity of the pivotal studies was hampered by the use of surrogate primary outcomes and the absence of recruitment information. To quantify drug treatment effect sizes, the reimbursement agencies primarily used data from another source in indirect comparisons. TLV granted reimbursement in five cases, compared with five in five cases for SMC and four in five cases for NICE. Decision modifiers, contributing to granted reimbursement despite hugely uncertain cost-effectiveness ratios, were e.g. small population size, occasionally linked to budget impact, severity of disease, end of life, and improved life expectancy.

Conclusion

For drugs whose authorization is based on prospective case series, most applications for reimbursement within public health care are granted. The underlying evidence has limitations over and above the design per se, and decision modifiers are frequently referred to in the value-based pricing decision making.

http://ift.tt/2Fwhptt

Integrating data from the IMPD/IB. A new tool for translational integration of preclinical effects.

The first administration of a new compound in humans is an important milestone. A major source of information for the researcher is the 'investigator's brochure' (IB). Such a document, has a size of several hundred pages. The IB should enable investigators or regulators to independently assess the risk-benefit of the proposed trial but the size and complexity makes this difficult. This article offers a practical tool for the integration and subsequent communication of the complex information from the IB or other relevant data sources. This paper is accompanied by an accessible software tool to construct a single page colour coded overview of preclinical and clinical data.

http://ift.tt/2DWMj0Z

Time-to-event modelling of effect of codrituzumab on overall survival in patients with hepatocellular carcinoma

Aims

Codrituzumab (GC33) is a recombinant, humanized mAb that binds to glypican-3 (GPC3), an oncofoetal protein highly expressed in hepatocellular carcinoma (HCC). This investigation aimed to identify clinically relevant factors that may affect the overall survival (OS) in HCC patients treated with codrituzumab and to quantitatively annotate their effects.

Methods

Codrituzumab exposure was estimated by a population pharmacokinetics model with a non-linear elimination pathway. Analysis of OS was performed using a time-to-event model in 181 patients with advanced HCC. The model was tested with addition of various covariates, including levels of immune biomarkers, such as CD16 (measured in terms of molecules of equivalent soluble fluorophore; CD16_MESF) and CD4, codrituzumab exposure, and potential prognostic biomarkers of HCC such as baseline tumour size, and soluble GPC3.

Results

The time-to-event model estimated a prolonged OS (>3 months) in patients with codrituzumab exposure of ≥230 μg/mL and high CD16_MESF level (>5.26 × 10⁵ MESF at least). The Weibull model was selected as the base hazard model. The baseline tumour size was included in the hazard model as a parameter independent of the drug effect. A logistic model was applied to explain the effects of drug exposure and CD16_MESF level.

Conclusions

The final model indicates that adequate drug exposure plus a favourable immune environment are associated with prolonged OS. This quantitative model should be further validated with emerging data so as to guide study design in future clinical trials.

http://ift.tt/2FrTc7C

Physical, chemical, and sensory properties of biscuits prepared from flour blends of unripe cooking banana, pigeon pea, and sweet potato

Abstract

Biscuits were produced from 14 flour blends of cooking banana (UBF), pigeon pea (PPF), and sweet potato (SPF). The physical properties, nutrient composition, and sensory characteristics of the biscuits were evaluated using standard methods. Data obtained were subjected to analysis of variance, and mean values were separated using Duncan's multiple range test. The hardness of the biscuit samples decreased as PPF increased, while the fracturability decreased with increase in UBF. Biscuits were significantly (p < .05) different in their nutrient composition, with the crude protein, crude fiber, ash contents, and dietary fiber content increasing as the PPF level increased. Cookies were rich in magnesium (576.54–735.06 mg/100 g) with favorable Na/K ratio (<1.0). The antinutritional factors in the biscuit samples were within permissible levels. Biscuits prepared from flour blend of 21.67% unripe cooking banana, 21.67% pigeon pea, and 56.67% sweet potato were the most preferred in terms of shape, mouthfeel, taste, crunchiness, and overall acceptability. Flour blends of unripe cooking banana, pigeon pea, and sweet potato could therefore be used as raw materials for the production of biscuits, with high protein, total dietary, and energy content.

The quality attributes of biscuits prepared from flour blends of cooking banana (UBF), pigeon pea (PPF), and sweet potato (SPF) were investigated. Biscuits were significantly (p < .05) different in their nutrient composition, with the crude protein, crude fiber, ash, and dietary fiber contents increasing as the PPF level increased. Biscuit prepared from flour blend of 21.67% unripe cooking banana, 21.67% pigeon pea, and 56.67% sweet potato was the most preferred in terms of shape, mouthfeel, taste, crunchiness, and overall acceptability.

http://ift.tt/2Eoo49L

Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia

Abstract

Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28–37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50–33 thousand years ago (kya), followed by East Asian (~ 40–15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.

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Crosstalk between TGF-β signaling and epigenome

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Spotlight on… Emmanuelle Charpentier

Biographical Summary

Emmanuelle Charpentier is a French microbiologist, geneticist and biochemist. She is a Director at the Max Planck Institute for Infection Biology in Berlin, Honorary Professor at Humboldt University, Visiting Professor at Umeå University and recipient of an Alexander von Humboldt Professorship. Prior to her current appointments, she worked at several other institutions in Germany, Sweden, Austria, the US and France. Emmanuelle Charpentier's research on a bacterial immune system laid the foundation for the ground-breaking CRISPR-Cas9 genome engineering technology. She has received numerous prestigious awards and distinctions, and is an elected member of several renowned academies of sciences. She is co-founder of CRISPR Therapeutics and ERS Genomics.

http://ift.tt/2FtaBww