Δευτέρα 19 Νοεμβρίου 2018
The 53rd Congress of the European Society for Surgical Research
Eur Surg Res 2018;59:1–103
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Role of Positron Emission Tomography/Computed Tomography in Preoperative Assessment of Carcinoma Endometrium—a Retrospective Analysis
Abstract
PET/CT has made significant inroads into routine oncological practice in recent times. In our study, we aim to determine its value in preoperative assessment of endometrial carcinoma. A retrospective study between January 2011 and March 2016 was conducted; we included all cases of carcinoma endometrium with a preoperative PET/CT scan. PET/CT images were analyzed and correlated with histological findings after surgical staging. A total of 46 cases were analyzed, mean age was 59.8 years, BMI 30.8 kg/m2, and most common histology endometrioid type (69.5%). We correlated PET/CT findings with histopathology as reference standard. PET/CT had a sensitivity of 40%, moderate specificity (75%) and accuracy (71.7%), good NPV (91.2%), but poor PPV (16.7%) for lymph node involvement. A total of 10 (21.7%) cases were detected to have distant metabolically active lesions on PET/CT, seven out of these were positive for malignancy. And 90% of them were either non-endometrioid type or grade two and higher. We found that SUV of primary tumor was significantly higher in patients with deep myometrial invasion (p = 0.018), and high-risk histological type of tumor (p = 0.022), though not statistically significant when lymph nodal involvement (p = 0.9), cervical involvement (p = 0.56), or histological grade (p = 0.84) were considered. Sensitivity and specificity of PET/CT in staging endometrial cancer is not high enough to reliably tailor lymphadenectomy. Although SUV of the primary tumor was significantly higher in patients with deep myometrial invasion and high-risk histological type, it's usefulness in classifying patients into predefined risk groups seems to be limited. However, it is useful in detecting distant metastasis especially in high-grade and non-endometrioid type of tumors. Thus, implementation of PET/CT as a surrogate for surgical staging of endometrial cancer remains enigmatic and is open to further research.
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Suppressed OGT expression inhibits cell proliferation while inducing cell apoptosis in bladder cancer
Abstract
Background
This study aimed to explore hyper-O-linked N-acetylglucosaminylation (O-GlcNAcylation) with an elevation of the expression of O-linked-β-N-acetylglucosamine transferase (OGT) in human bladder cancer.
Methods
Immunohistochemical staining for OGT and O-GlcNAcylation was performed in 20 paired human bladder cancer and adjacent normal tissues, as well as in human bladder cancer tissue microarrays (N = 169). The expression level of OGT and O-GlcNAcylation in cell lines were detected using the Western blot analysis. The effects of O-GlcNAcylation on the cell proliferation of bladder cancer were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clone formation assays. Cell apoptosis and cell cycle analysis were detected using flow cytometry. The autophagy of bladder cancer cells was investigated using the Western blot analysis, and GFP–LC3 plasmid was used to detect the autophagic flux. MTT assay was performed to detect the sensitivity of bladder cancer cells to cisplatin after OGT knockdown.
Results
The expression of OGT and the O-GlcNAcylation were upregulated in bladder cancer tissues and cell lines. O-GlcNAcylation and OGT were observed in nucleus and cytoplasm and found to be higher in muscle-invasive bladder cancer (MIBC) than in non-muscle-invasive bladder cancer (NMIBC). Reducing hyper-O-GlcNAcylation by OGT knockdown inhibited the proliferation of bladder cancer cells in vitro and xenograft tumor growth in vivo, triggered apoptosis, as well as led to cell cycle arrest. It also increased autophagy in bladder cancer cells. This study demonstrated increased autophagy pro-survival, but not pro-death. Reducing hyper-O-GlcNAcylation by OGT knockdown facilitated the chemosensitivity of bladder cancer cells to cis-platinum.
Conclusions
The data indicated that hyper-O-GlcNAcylation enhanced oncogenic phenotypes and was involved in DNA damage response in bladder cancer.
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Long-term survival and late complications of intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma
Abstract
Background
To evaluate the effectiveness and toxicities of intensity-modulated radiotherapy (IMRT) for locally recurrent nasopharyngeal carcinoma (NPC).
Methods
One hundred and eighty-four previously irradiated NPC patients with recurrent disease and re-irradiated by IMRT between February 2005 to May 2013 had been reviewed. The disease was re-staged I in 33, II in 27, III in 70 and IV in 54 patients. Seventy-five percent of the patients received cisplatin-based chemotherapy.
Results
The median survival time was 33 months. The 3-year actuarial rates of local recurrence–free survival (LRFS), distant metastases–free survival (DMFS), and overall survival (OS) rates were 85.1, 91.1, and 46.0%, respectively. About 53% of the patients experienced Grade 3–4 late toxicities. Forty-four patients died of massive hemorrhage of the nasopharynx caused by radiation induced mucosal necrosis. Multivariate analysis indicated that chemotherapy and time interval between initial radiotherapy and re-irradiation were independent predictors for DMFS.
Conclusion
IMRT is an effective method for patients with locally recurrent NPC. Massive hemorrhage of the nasopharynx is the major sever late complication and also the leading cause of death. Early recurrence is negative factor for DMFS. Combination of chemotherapy can improve DMFS, but not for OS. Optimal salvage treatment strategies focusing on improvement of survival and minimization of late toxicities are warranted.
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Study protocol: a randomized control trial of African American families fighting parental cancer together
Abstract
Background
African American adults experience a disproportionate burden and increased mortality for most solid tumor cancers and their adolescent children are negatively impacted by the illness experience. The purpose of this randomized clinical trial is to evaluate the efficacy of a culturally sensitive family-based intervention program developed for African American families coping with solid tumor parental cancer using an intention-to-treat approach. Primary outcome is adolescent depressive symptoms at end of treatment.
Methods
A sample of 172 African American families will be enrolled from two diverse oncology centers (Helen Graham Cancer Center in Newark, DE, and Kimmel Cancer Center in Philadelphia, PA). Eligible families will be randomized either to a 5-session intervention Families Fighting Cancer Together (FFCT) or a 5-session parent-only psycho-educational (PED) program. Assessments will occur at weeks 0 (baseline), 8 (end-of-treatment), 24, and 52.
Discussion
Treatments to help African American adolescents cope with the impact of parental cancer are scarce and urgently needed. If successful, this proposed research will change the nature of intervention support options available to African Americans, who are overrepresented and underserved by existing services or programs.
Trial registration
This project is registered with ClinicalTrials.gov (Protocol #: NCT03567330).
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Population pharmacokinetics and exposure–response assessment of veliparib co-administered with temozolomide in patients with myeloid leukemias
Abstract
Purpose
Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design.
Methods
Population pharmacokinetic analysis was performed using Phoenix® NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CLCR), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival.
Results
A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CLCR and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure.
Conclusions
Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure–safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure–efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit–risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.
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A comparative evaluation of gemtuzumab ozogamicin + daunorubicin-cytarabine and other treatments for newly diagnosed acute myeloid leukemia
Future Oncology, Ahead of Print.
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Intraoperative radiation therapy for the treatment of recurrent retroperitoneal and pelvic tumors: a single-institution analysis
Abstract
Background
Patients with recurrent retroperitoneal and pelvic region tumors often require multimodal therapies. Intraoperative radiation therapy (IORT) can deliver high-dose radiation to tumor beds, even if first-line external beam radiation therapy (EBRT) was administered. We evaluated local control (LC) and survival in patients receiving IORT for recurrent tumors.
Methods
We retrospectively analyzed 41 patients with isolated pelvic or retroperitoneal recurrences of colorectal, gynecological, or retroperitoneal primary tumors. Following salvage surgery, all patients underwent tumor bed IORT via electron beam or high dose rate brachytherapy. Isolated IORT (median dose: 15 Gy) was administered to patients who had received first-line EBRT; other patients received IORT (median dose 12 Gy) plus EBRT. Local (LF), regional (RF), and distant failures (DF) were evaluated, and the Kaplan–Meier method and log-rank test were used to evaluate and compare overall survival (OS) from the date of IORT.
Results
Forty-one patients underwent 44 treatments, including 27 (61.3%) isolated IORT and 17 (38.7%) IORT and EBRT combination regimens. The median follow-up was 8.1 years (range: 4.4–11.7 years), and the 2, 5, and 8 year overall LC rates were 87.9, 64.0, and 49.8%, respectively. Regarding resection status, the respective 2, 5, and 8 year LC rates were 90, 76, and 76% for R0 resection and 75, 25, and 0% for R1 resection (p < 0.001). The 2, 5, and 8 year OS rates were 68, 43, and 26%, respectively. OS was better among patients with LC (p < 0.001). Twenty-four patients (58.5%) experienced a DF, and the 5 year OS rates for the patients with and without DF were 36 and 52%, respectively (p = 0.04).
In a multivariate analysis, LF (p = 0,012) and recurrent retroperitoneal sarcoma (p = 0,014) were identified as significant predictors of worse OS. Thirteen patients (31%) developed clinically treatable complications related to IORT.
Conclusions
Many patients achieve long-term OS and LC without significant morbidity after salvage surgery and IORT, especially in case of clear margins.
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Treatment of Rectal Cancer in Older Adults
Abstract
Purpose of Review
Rectal cancer is predominantly a disease of older adults but current guidelines do not incorporate the associated specific challenges leading to wide variation in the delivery of cancer care to this subset of population. Here, we will review the current data available regarding the management of rectal cancer in older adults.
Recent Findings
The greatest challenge arises in the management of stage II/III disease as it involves tri-modality treatment that can be harder to tolerate by frail older patients. Response to neoadjuvant treatment is being used as a new marker to tailor further therapy and possibly avoid surgery. Oxaliplatin can be omitted from the adjuvant treatment without compromising outcomes.
Summary
Physicians should perform geriatric assessment utilizing many validated tools available to help predict treatment tolerability and outcomes in older adults that can help personalize subsequent management. Most older adults can undergo standard therapy for stages I, II, or III rectal cancer with curative intent. Increasing evidence suggests that patients with a clinical complete response to neoadjuvant treatment may be observed closely with the possibility of avoiding surgery. Studies are evaluating alternate systemic treatments for advanced metastatic disease with the hope of maintaining quality of life without compromising cancer outcomes.
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Breast cancer and synchronous multiple primary lung adenocarcinomas with heterogeneous mutations: a case report
Abstract
Background
Multiple primary malignant tumors (MPMT) refers to the presence of two or more primary cancers of different organs in the same patient. MPMT is a sparse disease in the past, but there has been a gradual increase in the morbidity. Since multiple primary malignant tumors treatment methods differ, it is essential for clinicians to be able to distinguish between separate primary lesions and metastasis.
Case presentation
We present the case of a 57-year-old woman with MPMT presenting with cancer in the left breast and synchronous double primary lung adenocarcinomas. We used IHC and epidermal growth factor receptor(EGFR)mutation to analyze genomic alteration profiles in the patient to validate the difference among the pathological assessments and the clinical differences between double primary lesions of lung and breast. EGFR gene analysis of breast cancer lesion revealed no mutations. The left and right lower lobe lung adenocarcinomas contained EGFR gene mutations: an L858R point mutation in exon 21 in the left lesion and a deletion mutation in exon 19 in the right lesion. The breast cancer and both lung adenocarcinomas were surgically resected. To date, the patient has remained disease-free.
Conclusions
Both pathological and molecular assessment adapted in the current study appeared necessary. Mutational analysis of the EGFR gene provided important information not only in the diagnosis and but also in the treatment of MPMT.
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Analysis of implant loss risk factors especially in maxillary molar location: A retrospective study of 6977 implants in Chinese individuals
Abstract
Background
The knowledge of the potential risk factors associated with implant loss is crucial for dental clinicians, but the opinions about the risk factors are still diverse and controversial.
Purpose
This retrospective study assessed the risk factors associated with implant loss, especially that in the maxillary molar location.
Materials and Methods
From January 2015 to March 2017, 4338 Chinese patients received 6977 implants at Nanjing Stomatological Hospital. Information on patient age, gender, bone grafting procedure, implant location, length and diameter, and the records of lost implants were obtained. The Kaplan‐Meier method and log‐rank test were used to conduct a survival function analysis. Chi‐square test and multivariate Cox regression analysis were used to identify risk factors related to implant loss.
Results
The cumulative survival rate (CSR) after 0‐32 months of observation period for all implants was 97.76%, and the CSR for maxillary molar implants was 97.00%. Maxillary molar implants showed a significantly lower CSR than the other implants (P < .05). Male sex, short implants (<10 mm) were considered as risk factors for implant loss. However, male sex and bone grafting procedure were regarded as risk factors for maxillary molar implant loss, which was slightly different from the result of all implants.
Conclusions
Male sex, short implants (<10 mm) and maxillary molar location were considered as potential risk factors for implant loss, whereas male sex and bone grafting procedure were significantly associated with implant loss in maxillary molar location.
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The role of therapeutic drug monitoring in treatment optimization in tuberculosis and diabetes mellitus co-morbidity [Letters]
With great interest we read the paper by Alfarisi et al reporting the effects of diabetes mellitus (DM) on the pharmacokinetics and pharmacodynamics of tuberculosis treatment (1)....
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Evaluation of carbapenems for multi/extensive-drug resistant Mycobacterium tuberculosis treatment [Pharmacology]
M/XDR-TB has become an increasing threat in high burden countries but also in affluent regions due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of M. tuberculosis. To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo and clinical data on carbapenems in the treatment of M. tuberculosis and detection of knowledge gaps, in order to target future research.
In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and lab strains of M. tuberculosis, are consistent. In vitro the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore is it practically impossible to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, one prospective, two observational and seven retrospective clinical studies to assess effectiveness, safety and tolerability of three different carbapenems (imipenem, meropenem and ertapenem). Presently we found no clear evidence to select one particular carbapenem among the different candidate compounds, to design an effective M/XDR-TB regimen. Therefore more clinical evidence and dose optimization substantiated by hollow fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.
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Inhibitors of Signaling Pathways that Block Reversal of HIV-1 Latency [Antiviral Agents]
Signaling pathways play a key role in HIV-1 latency. In this study, we used the 24ST1NLESG cell line of HIV-1 latency to screen a library of structurally diverse, medicinally active, cell permeable kinase inhibitors, which target a wide range of signaling pathways, to identify inhibitors of HIV-1 latency reversal. The screen was carried-out in the absence or presence of three mechanistically distinct latency reversing agents (LRAs), namely prostratin, panobinostat and JQ-1. We identified inhibitors that only blocked the activity of a specific LRA, as well as inhibitors that blocked the activity of all LRAs. For example, we identified 12 inhibitors targeted toward protein kinase C or downstream kinases that blocked the activity of prostratin. We also identified 12 kinase inhibitors that blocked reversal of HIV-1 latency irrespective of the LRA used in the screen. Of these danusertib, an Aurora kinase inhibitor, and PF-3758309, a PAK4 inhibitor, were the most potent. The 50% inhibitory concentrations in the 24ST1NLESG cells ranged from 40-147 nM for danusertib (selectivity indices >150) and from 0.1-1nM for PF-3758309 (selectivity indices >3,300). Both danusertib and PF-3758309 inhibited latency reversal in CD4+ T cells isolated from HIV-1-infected donors. Collectively, our study describes a chemical approach that can be applied to elucidate the role of signaling pathways involved in LRA activity, or the maintenance of HIV-1 latency; and also identifies inhibitors of latent HIV-1 reactivation that could be used with antiretroviral therapy to reduce residual viremia.
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Population Pharmacokinetics of Mefloquine Intermittent Preventive Treatment for Malaria in Pregnancy in Gabon [Pharmacology]
Introduction Mefloquine is evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and its metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated and potential covariates influencing the pharmacokinetic properties were assessed.
Materials and Methods A population pharmacokinetic analysis was performed with 264 pregnant women of a randomized controlled trial evaluating a single and split-dose regimen of two 15 mg/kg mefloquine dosings at least one month separated versus SP-IPTp. Both mefloquine enantiomers and its carboxy-metabolite (CMQ), measured in plasma and cord, were applied for pharmacokinetic modelling using NONMEM 7.3.
Results Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group the mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated (r2=0.84) at delivery. With the investigated dosing regimens prophylactic levels are not constantly achieved. A modelling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented.
Discussion This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens, however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as valuable tool for researchers and clinicians to develop and optimise alternative dosing regimens for IPTp in pregnant women.
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The Role of Rifampin against Staphylococcal Biofilm Infections in Vitro, in Animal Models, and in Orthopedic Device-Related Infections. [Minireviews]
Rifampin has been used as an agent in combination therapy in orthopedic device-related infections (ODRI) for almost three decades. The aim of this review is to provide data regarding the role of rifampin against biofilm infection in vitro, in animal models, and in clinical ODRI. Available data are gathered in order to present the rational use of rifampin combinations in patients with periprosthetic joint infection (PJI). In-vitro data, animal data and available clinical data in the field of staphylococcal PJI will be reviewed. The role of rifampin is well-defined in patients with PJI and is indicated in those who fulfill the Infectious Diseases Society of America criteria for debridement and implant retention or one-stage exchange. It should be used with care because of the danger of rapid emergence of resistance. Potential drug interactions should be considered.
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In-vivo gentamicin susceptibility test for prevention of bacterial biofilms in bone tissue and on implants [Susceptibility]
Objectives: To set up an in-vivo gentamicin susceptibility test for biofilm prevention in bone tissue and on implants.
Methods: Twenty-five pigs were allocated to six groups. Group A (n=6) was inoculated with saline. Groups B (n=6), C (n=3), D (n=3), E (n=3) and F (n=4) were inoculated with 10 μL saline containing 104 CFU of Staphylococcus aureus. Different concentrations based on the minimal inhibitory concentrations (MIC) of gentamicin to the specific strain were added to the 10 μL inoculum of Groups C (160xMIC), D (1,600xMIC), E (16,000xMIC) and F (160,000xMIC). The inoculums were injected into a pre-drilled tibial implant cavity followed by insertion of a steel implant (2 x 15 mm). The pigs were euthanized after five days. In-vitro, all the used doses were found bacteriostatic after up to 6 hours.
Results: All implant cavities of pigs inoculated with bacteria and bacteria + 160xMIC or 1,600xMIC were positive for S. aureus. In each of the Groups E (16,000xMIC) and F (160,000xMIC) 2/3 and 1/4 of the implant cavities were S. aureus positive, respectively. By grouping Groups C + D (<10,000xMIC) and Groups E + F (>10,000xMIC) a significant decrease of implant attached bacteria was only seen between the high MIC value group and Group B. Histologically, it was demonstrated that 1,600, 16,000 and 160,000 x MIC resulted in a peri-implant tissue reaction comparable to saline inoculated animals.
Conclusion: In-vivo, the antimicrobial tolerance of the inoculated planktonic bacteria was increased by in-vivo specific factors of acute inflammation. This resulted in bacterial aggregation and biofilm formation which further increased the gentamicin tolerance. Thus, susceptibility patterns in-vitro might not reflect the actual in-vivo susceptibility locally within a developing infectious area.
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A diagnostic algorithm to investigate pyrazinamide and ethambutol resistance in rifampicin resistant Mycobacterium tuberculosis isolates in a low incidence setting [Susceptibility]
Phenotypic drug susceptibility testing (DST) for the two first-line tuberculosis drugs ethambutol and pyrazinamide is known to yield unreliable and inaccurate results. In this prospective study, we propose a diagnostic algorithm combining phenotypic DST with Sanger sequencing to inform clinical decision-making for drug resistant Mycobacterium tuberculosis complex isolates. Sequencing results were validated using whole genome sequences (WGS) of the isolates. Resistance-conferring mutations obtained by pncA sequencing correlated well with phenotypic DST results for pyrazinamide. Phenotypic resistance to ethambutol was only partly explained by mutations in the embB 306 codon. Additional resistance conferring mutations were found in the embB gene at codons 354, 406 and 497. In several isolates that tested ethambutol susceptible by phenotypic DTS, well-known resistance conferring embB mutations were determined. Thus, targeted Sanger sequencing beyond embB 306 codon or WGS together with phenotypic DST should be employed to ensure reliable ethambutol drug susceptibility as basis for rational design of MDR-TB regimens with or without ethambutol.
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Identification of a novel gene associated with high-level {beta}-lactam resistance in heterogeneous vancomycin-intermediate Staphylococcus aureus strain Mu3 and methicillin-resistant S. aureus strain N315 [Mechanisms of Resistance]
β-lactam resistance levels vary among methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, mediated by chromosomal mutations and exogenous resistance gene mecA. However, MRSA resistance mechanisms are incompletely understood. A P440L mutation in the RNA polymerase β' subunit (RpoC) in slow-vancomyicn-intermediate S. aureus (sVISA) strain V6-5 is associated with conversion of heterogeneous VISA (hVISA) to sVISA. Herein, we found a V6-5-derivative strain (L4) with significantly decreased MICs to oxacillin (OX) and vancomycin. Whole-genome sequencing revealed that L4 has nonsense mutations in two genes, relQ encoding (p)ppGpp synthetase, an alarmone of the stringent response, and a gene of unknown function. relQ deletion in the hVISA strain Mu3 did not affect OX MIC. However, introducing nonsense mutation of the unknown gene into Mu3 decreased OX MIC, whereas wild-type gene recovered high-level resistance. Thus, mutation of this unknown gene (ehoM) decreased β-lactam resistance in Mu3 and L4. Presence of relQ in a multi-copy plasmid restored high-level resistance in strain L4 but not in the ehoM mutant Mu3 strain, indicating a genetic interaction between ehoM and relQ depending on the L4 genetic background. While mupirocin (stringent response inducer) can increase the β-lactam resistance of MRSA, mupirocin supplementation in an ehoM deletion mutant of N315 did not elevate resistance. ehoM expression in N315 was induced by mupirocin, and the relative amount of ehoM transcript in Mu3 was higher than in N315 induced by the stringent response. Our findings indicate that ehoM plays an essential role in high-level β-lactam resistance in MRSA via the stringent response.
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APX001 is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis [Experimental Therapeutics]
Invasive pulmonary aspergillosis (IPA) due to Aspergillus fumigatus is a serious fungal infection in the immunosuppressed patient population. Despite the introduction of new antifungal agents, mortality rates remain high and new treatments are needed. The novel antifungal APX001A targets the conserved Gwt1 enzyme required for the localization of glycosylphosphatidyl inositol (GPI)-anchored mannoproteins in fungi. We evaluated the in vitro activity of APX001A against A. fumigatus and the in vivo activity of its prodrug APX001 in an immunosuppressed mouse model of IPA. APX001A inhibited the growth of A. fumigatus with a minimum effective concentration (MEC) of 0.03 μg/ml. The use of 50 mg/kg 1-aminobenzotriazole (ABT), a suicide inhibitor of cytochrome P450 (CYP) enzymes, enhanced APX001A exposures (AUC) 16- to 18-fold and enhanced serum half-life from ~1 to 9 h, more closely mimicking human pharmacokinetics. We evaluated the efficacy of APX001 (with ABT) in treating murine IPA as compared to posaconazole treatment. Treatment of mice with 78 mg/kg QD, 78 mg/kg BID, or 104 mg/kg QD APX001 significantly enhanced median survival time and prolonged Day 21 post-infection overall survival when compared to placebo. Furthermore, administration of APX001 resulted in a significant reduction in lung fungal burden (4.2 to 7.6 log10 conidial equivalents/gram tissue) vs the untreated control and resolved the infection as judged by histopathological examination. The observed survival and tissue clearance were comparable to a clinically relevant posaconazole dose. These results warrant the continued development of APX001 as a broad spectrum, first in class treatment for invasive fungal infections.
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Pre-Exposure to Isavuconazole Increases the Virulence of Mucorales but not Aspergillus fumigatus in a Drosophila melanogaster Infection Model [Clinical Therapeutics]
Breakthrough mucormycosis in patients receiving isavuconazole prophylaxis or therapy has been reported. We compared the impact of isavuconazole and voriconazole exposure on the virulence of clinical isolates of Aspergillus fumigatus and different Mucorales species in a Drosophila melanogaster infection model. In contrast to A. fumigatus, a hyper-virulent phenotype was found in all tested Mucorales upon pre-exposure to either voriconazole or isavuconazole. These findings may contribute to the explanation of breakthrough mucormycosis in isavuconazole-treated patients.
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ERG6 and ERG2 are major targets conferring reduced susceptibility to amphotericin B in clinical Candida glabrata isolates in Kuwait [Mechanisms of Resistance]
Candida glabrata is intrinsically less susceptible to azoles and resistance to echinocandins and reduced susceptibility to amphotericin B has also been detected. Molecular mechanisms of reduced susceptibility (RS) to amphotericin B (AMB) were investigated in C. glabrata strains in Kuwait by sequence analyses of genes involved in ergosterol biosynthesis. A total of 1646 C. glabrata isolates were tested by Etest and results for 12 selected isolates were confirmed by reference broth microdilution. PCR-sequencing of three (ERG2, ERG6 and ERG11) genes was performed for all RS-AMB and 5 selected wild-type C. glabrata isolates by using gene-specific primers. Total cell sterol content was analyzed by gas chromatography-mass spectrometry. Phylogenetic relationship among the isolates was investigated by multilocus sequence typing. Wild-type isolates contained only synonymous mutations in ERG2, ERG6 or ERG11 and total sterol content was similar to reference strains. A nonsynonymous (AGA48AAA, R48K) ERG6 mutation was found in both RS-AMB and wild-type isolates. Four RS-AMB isolates contained novel nonsense mutations at Trp286/Tyr192/Leu341 and 2 isolates contained nonsynonymous (V126F or C198F) mutation in ERG6 and their sterol content were consistent with ERG6 deficiency. Two other RS-AMB isolates contained a novel nonsynonymous (G119S or G122S) ERG2 mutation and their sterol content were consistent with ERG2 deficiency. Of 8 RS-AMB isolates, 1 fluconazole-resistant isolate also contained nonsynonymous Y141H+L381M mutations while 7 isolates contained only synonymous mutations in ERG11. All isolates with ERG6/ERG2/ERG11 mutations were genotypically distinct strains. Our data show that ERG6 and ERG2 are major targets conferring RS-AMB in clinical C. glabrata isolates.
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Host cell metabolism contributes to delayed-death kinetics of apicoplast inhibitors in Toxoplasma gondii [Mechanisms of Action]
Toxoplasma gondii and related human parasites contain an essential plastid organelle called the apicoplast. Clinically-used antibiotics and other inhibitors that disrupt apicoplast biogenesis cause a mysterious "delayed-death" phenotype in which parasite growth is unaffected during the first lytic cycle of inhibitor treatment but is severely inhibited in the second lytic cycle even after drug removal. Critical to understanding the complex downstream cellular effects of these drug classes is the timing of apicoplast loss during inhibitor treatment and how it relates to this peculiar growth phenotype. Here we show that, upon treatment with diverse classes of apicoplast inhibitors, newly-replicated T. gondii parasites in the first lytic cycle initially form apicoplasts with defects in protein import or genome replication and eventually fail to inherit the apicoplast altogether. Despite the accumulation of parasites with defective or missing apicoplasts, growth is unaffected during the first lytic cycle, as previously observed. Strikingly, concomitant inhibition of host cell isoprenoid biosynthesis results in growth inhibition in the first lytic cycle and unmasks the apicoplast defects. These results suggest that defects in and even complete loss of the apicoplast in T. gondii are partially rescued by scavenging of host cell metabolites leading to death that is delayed. Our findings uncover host cell interactions that can alleviate apicoplast inhibition and highlight key differences in "delayed-death" inhibitors between T. gondii and Plasmodium falciparum.
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Genetic mechanisms behind the spread of reduced susceptibility to azithromycin in Shigella isolated from men who have sex with men, in Quebec, Canada [Mechanisms of Resistance]
We analysed 254 Shigella spp., isolates collected in Québec, Canada, during 2013-2014. Overall, 23.6% of isolates showed reduced susceptibility to azithromycin (RSA) encoded by mphA (11.6%), ermB (1.7%) or by both genes (86.7%). Shigella strains with RSA were mostly isolated from men who have sex with men (68.8% or higher) from the Montreal region. Complete sequence analysis of six selected plasmids from Shigella sonnei and different serotypes of Shigella flexneri emphasized the role of IS26 in RSA dissemination.
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Impact of Antifungal Compounds on Viability and Anti-Aspergillus Activity of Human Natural Killer Cells [Experimental Therapeutics]
Despite the availability of new antifungal compounds, invasive aspergillosis carries high morbidity and mortality in hematopoietic stem cell transplant recipients. In vitro studies and animal models suggest that the adoptive transfer of Natural Killer (NK) cells could be a promising immunotherapeutic option in this setting. As it is unclear whether viability and function of human NK cells are affected by common antifungal agents, we analyzed the interaction of various concentrations of amphotericin B-deoxycholate (AmB-D), liposomal amphotericin B, caspofungin, fluconazole, voriconazole, and posaconazole with human NK cells. When adding NK cells to therapeutic concentrations of antifungal agents, a significant increase of the antifungal effect was seen for caspofungin and voriconazole, whereas NK cells significantly decreased the hyphal damage of escalated doses of AmB-D. In contrast, therapeutic concentrations of all antifungal compounds tested did not have a negative effect on proliferation, viability, and the release of soluble immunomodulatory molecules of NK cells. These data indicate that therapeutic concentrations of the antifungal agents tested do not negatively affect the functional properties of human NK cells, which is a prerequisite for further studies evaluating NK cells as antifungal immunotherapy in immunocompromised patients suffering from invasive aspergillosis.
https://ift.tt/2zhJZhk
Omadacycline gut microbiome exposure does not induce Clostridium difficile proliferation or toxin production in a model that simulates the proximal, medial and distal human colon [Clinical Therapeutics]
A clinically reflective model of the human colon was used to investigate the effects of the broad-spectrum antibiotic omadacycline on the gut microbiome, and subsequent potential to induce simulated Clostridium difficile infection (CDI). Triple stage chemostat gut models were inoculated with pooled human faecal slurry from healthy volunteers (age ≥60 years). Models were challenged twice with 107 cfu C. difficile spores (PCR ribotype 027). Omadacycline effects were assessed in a single gut model. Observations were confirmed in a parallel study with omadacycline and moxifloxacin. Antibiotic instillation was performed once daily for 7 days. The models were observed for 3 weeks post-antibiotic challenge. Gut microbiota populations and C. difficile total viable and spore counts were enumerated daily by culture. Cytotoxin titres and antibiotic concentrations were also measured. Gut microbiota populations were stable before antibiotic challenge. Moxifloxacin instillation caused a ~4 log10 cfu/mL decline in enterococci and Bacteroides fragilis group populations, and a ~3 log10 cfu/mL decline in bifidobacteria and lactobacilli, followed by simulated CDI (vegetative cell proliferation and detectable toxin). In both models, omadacycline instillation decreased populations of bifidobacteria (~8 log10 cfu/mL), B. fragilis group populations (7-8 log10 cfu/mL), lactobacilli (2-6 log10 cfu/mL), and enterococci (4-6 log10 cfu/mL). Despite these microbial shifts, there was no evidence of C. difficile germination or toxin production. In contrast to moxifloxacin, omadacycline exposure did not facilitate simulated CDI, suggesting this antibiotic may have a low propensity to induce CDI in the clinical setting.
https://ift.tt/2OSt1eo
Fluconazole-Induced Alopecia: Examination in an animal model and human cohort [Mechanisms of Action]
Fluconazole-induced alopecia is a significant problem for patients receiving long-term therapy. We evaluated the hair-cycle changes of fluconazole in a rat model and investigated potential molecular mechanisms. Plasma and tissue levels of retinoic acid were not found causal. Human patients with alopecia attributed to fluconazole also underwent detailed assessment and in both our murine model and human cohort fluconazole induced telogen effluvium. Future work further examining the mechanism of fluconazole-induced alopecia should be undertaken.
https://ift.tt/2zhJWlE
Population pharmacokinetics and pharmacodynamics of bezlotoxumab in adults with primary and recurrent Clostridium difficile infection [Clinical Therapeutics]
The fully human monoclonal antibody bezlotoxumab is indicated for preventing recurrence of Clostridioides (formerly Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI and at high risk for CDI recurrence. The efficacy and safety of 10 mg/kg bezlotoxumab was demonstrated in two Phase 3 trials: MODIFY I (NCT01241552) and MODIFY II (NCT01513239). Here, a population pharmacokinetic (popPK) analysis is reported using data from MODIFY I and II (n=1515), and from three Phase 1 trials (n=72) to characterize bezlotoxumab PK in Phase 3 clinical trial participants and in healthy subjects. A stepwise covariate search was conducted to identify factors influencing PK. Post-hoc estimated bezlotoxumab exposures from the popPK model were used to conduct an exposure-response analysis for CDI recurrence.
Bezlotoxumab PK was described by a two-compartment model with linear elimination and allometric scaling for clearance and volume of distribution by body weight. Although the final popPK model included gender, ethnicity (Japanese descent), race (black vs non-black), and albumin level as significant covariates, the impact of these factors was not clinically meaningful based on the totality of PK and clinical experience.
Exposure-response analysis of CDI recurrence demonstrated a similar low rate of CDI recurrence over the entire range of exposures achieved in the Phase 3 trials, indicating that exposures were on the maximal response plateau of the exposure-response curve. Overall, the analyses confirmed the appropriateness of the 10 mg/kg dose across the Phase 3 population with no dose adjustments necessary over a broad demographic background.
https://ift.tt/2OSsVDy
Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication [Antiviral Agents]
Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell–derived astrocytes was less susceptible to sofosbuvir compared to the hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection–dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg/day, and prevented mortality in a neonate mouse model at 40 and 80 mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.
https://ift.tt/2zhJSlU
APX001 and Other Gwt1 inhibitor Prodrugs are Effective in Experimental Coccidioides immitis Pneumonia [Experimental Therapeutics]
Coccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, Coccidioides immitis, and C. posadasii that are endemic in the southwestern US and other areas in the Western Hemisphere. Chronic cavitary pulmonary infections and extra-pulmonary sites of infection are very difficult to treat and often require life-long azole therapy. APX001A is the first in a new class of broad spectrum antifungal agents which inhibit Gwt1, an enzyme which is required for localization of glycosylphosphatidyl inositol (GPI)-anchored mannoproteins in fungi. APX001A and several analogs were highly active against clinical isolates of Coccidioides, inhibiting hyphal growth at low nanogram/ml concentrations. APX001 is the N-phosphonooxymethyl prodrug of APX001A, currently in clinical trials for the treatment of invasive fungal infections. Mice were treated orally once-daily with 26 mg/kg/day of APX001 and the prodrug analog APX2097, two hours after administration of the pan-cytochrome P450 inhibitor 1-aminobenzotriazole, which was used to enhance drug half-life and exposures to more closely mimic human pharmacokinetics of APX001A. Five days of treatment reduced lung colony counts by nearly 3 logs and prevented dissemination, similar to the efficacy of fluconazole dosed orally at 25 mg/kg twice daily. In a survival experiment, both APX001 and APX2097-treated mice survived significantly longer than control and fluconazole treated mice. APX001 and other members of this new class of antifungal agents may offer great promise as effective therapies for coccidioidomycosis.
https://ift.tt/2OPHLe8
Escalated radiation and prophylactic extended field nodal irradiation are beneficial for FIGO IIIB cervical cancer patients’ prognosis
Abstract
Background
Currently, the standard treatment for locally advanced cervical cancer patients is concurrent chemoradiotherapy. Here we aim to evaluate therapeutic efficacy, treatment failure, toxicity and prognostic factors for FIGO IIIB cervical cancer patients.
Methods
A comprehensive retrospective analysis was performed to understand various factors which contribute to IIIB cervical cancer prognosis. In total 223 well defined patients were assigned according to their pathological subtype, age, pre-treatment HGB level, tumor size, pelvic lymph node (LN) metastasis, para-aortic LN metastasis as well as external irradiation technologies, treatment duration, point A EQD2 dose and concurrent chemotherapy cycles. We then performed correlation studies of these factors and OS, DFS, LCR, DMFS using univariate and multivariate analysis respectively.
Results
We managed to achieve 207 (92.8%) complete response (CR) and 16 (7.2%) partial response (PR) with acceptable adverse effects. Notably, the 5 years OS, DFS, LCR, DMFS for these patients were 61.1, 55.2, 83.6 and 66.4% respectively. Importantly, our studies suggest that escalated point A EQD2 can significantly improve OS, DFS and LCR for FIGO IIIB cervical cancer patients, furthermore, patients without para-aortic LN metastasis who received prophylactic extended field irradiation have significant survival advantage for DFS and a tendency to improve OS and DMFS.
Conclusions
Our results suggest that FIGO IIIB cervical cancer patients should receive higher EQD2 (≥98Gy10) radiotherapy, moreover, patients without para-aortic LN metastasis should receive prophylactic extended field nodal irradiation to improve prognosis.
https://ift.tt/2Fwuub0
Olaparib Tablet: A Review in Ovarian Cancer Maintenance Therapy
Abstract
Olaparib (Lynparza®), a first-in-class poly (ADP-ribose) polymerase (PARP) inhibitor, has recently been approved in a new tablet formulation as maintenance treatment for recurrent high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy. Relative to an earlier capsule formulation, the tablet formulation of olaparib has improved bioavailability, thereby reducing pill burden and offering a more convenient dosage regimen. In the phase III SOLO2 study, maintenance treatment with olaparib tablets significantly prolonged median PFS (primary endpoint) relative to placebo in patients with platinum-sensitive, recurrent, ovarian cancer bearing gBRCA mutations. Results from an earlier phase II study (Study 19) assessing the capsule formulation supported these findings, with a significant PFS benefit (primary endpoint) observed with olaparib relative to placebo as maintenance therapy in patients with platinum-sensitive, recurrent, ovarian cancer, with or without BRCA mutations. Olaparib tablet had a manageable tolerability profile, with most adverse events of mild or moderate severity. Given its efficacy and manageable tolerability profile, olaparib tablets provide a useful maintenance treatment option for recurrent, platinum-sensitive ovarian cancer, regardless of BRCA mutation status, with the tablet formulation providing a more convenient dosing option.
https://ift.tt/2PCmbyQ
DNA damage response gene alterations in urothelial cancer: ready for practice?
Cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy is standard in fit patients. Inactivating mutations of the nucleotide excision repair gene, ERCC2, can predict response to cisplatin-based chemotherapy. Evaluation of the functional impact of ERCC2 mutations can provide mechanistic frameworks supporting the potential predictive role of ERCC2 loss of function.
https://ift.tt/2qWZWoM
Selective rickets from localized advanced maturation—a case report
Abstract
An unusual cause of rickets is illustrated by a patient with infantile multisystem inflammatory disease who, by age 2 years and 4 months, developed striking radiographic and clinical rickets restricted to those joints involved by the inflammatory process. The locally increased vascularity from his inflammation led to increased maturation at those sites so rapid as to override the usual enchondral calcification, thus causing a rickets pattern. Other sites, such as the proximal humeri, lacking any inflammation, showed no increased maturation rate and did not manifest local rickets. Rapid local bone maturation may cause localized rickets.
https://ift.tt/2zd4ewL
Phytochemical profiles and classification of Agave syrups using 1H‐NMR and chemometrics
Agave syrups are newly natural sweeteners. The phytochemical screening stands out for Agave syrups containing higher levels of metabolites with antioxidant activity. 1H‐NMR and chemometrics can be used for identified, differentiated, and classified Agave syrups.
Abstract
Background
Agave syrups are natural sweeteners that are highly desirable for human consumption because they have low glycemic index. In this work, we explored the potential of 1H‐NMR‐Chemometrics as a useful tool in the identification and differentiation of Agave syrups. Also, we evaluated the phytochemical screening and antioxidant capacity of Agave syrup compared to other natural sweeteners.
Results
The phytochemical screening stands out for Agave syrups containing higher levels of metabolites with antioxidant activity, mainly saponins, glycosides, and terpenoids. Agave syrup antioxidant activity was in a range from 10% to 53%, while the total phenolic content was from 24 to 300 EAG/100 g, and condensed tannins were between 240 and 1,900 mg CE/g. Additionally, 1H‐NMR spectroscopy was used to characterize syrup profiles and chemometrics. PCA group analyses allowed the sweeteners' classification by origin and kind of Agave.
Conclusion
Thus, we conclude that 1H‐NMR and chemometrics can be used for identifying, differentiating, and classifying Agave syrups. Besides, Agave syrups contain significant amounts of antioxidative components and can be considered as an effective source of antioxidant.
https://ift.tt/2A5lNyw
11th Child Dies in Adenovirus Outbreak at N.J. Care Facility
MONDAY, Nov. 19, 2018 -- An 11th child has died in an outbreak of a respiratory virus at the Wanaque Center for Nursing and Rehabilitation in New Jersey, health officials say. The "severely ill child" had the adenovirus infection and died Thursday...
https://ift.tt/2A5bDOc
Cap'n Crunch Cereal Recalled Due to Salmonella Scare
MONDAY, Nov. 19, 2018 -- A small number of boxes of Cap'n Crunch's Peanut Butter Crunch are being recalled due to potential Salmonella contamination, Quaker Oats says. The recall is for 21 boxes bought after Nov. 5 at Super Target Stores in Omaha...
https://ift.tt/2TsuV92
FDA Approves First-Line Tx for Peripheral T-Cell Lymphoma
MONDAY, Nov. 19, 2018 -- The U.S. Food and Drug Administration on Friday expanded approval for the use of Adcetris (brentuximab vedotin) injection in combination with chemotherapy for adult patients with specific types of peripheral T-cell lymphoma...
https://ift.tt/2A3Q1BZ
Even With Standing Orders, Naloxone Access Varies
MONDAY, Nov. 19, 2018 -- There are great differences in access to naloxone even among states that have passed legislation to allow pharmacists to dispense the medication without a physician's prescription, according to two research letters published...
https://ift.tt/2TsuUC0
FDA Warns Against Giving Honey-Filled Pacifiers to Infants
MONDAY, Nov. 19, 2018 -- Pacifiers filled with or dipped in honey should not be given to infants, the U.S. Food and Drug Administration says. The agency issued the warning after receiving reports of four infants in Texas who were hospitalized with...
https://ift.tt/2A3Q14X
Quasispecies Changes with Distinctive Point Mutations in the Hepatitis C Virus Internal Ribosome Entry Site (IRES) Derived from PBMCs and Plasma
The 5' untranslated region (UTR) of the hepatitis C virus (HCV) genome contains the internal ribosome entry site (IRES), a highly conserved RNA structure essential for cap-independent translation of the viral polyprotein. HCV, apart from the liver, is thought to be associated with lymphocyte subpopulations of peripheral blood mononuclear cells (PBMCs), in lymph nodes and brain tissue. In this study, RT-PCR, cloning, and sequence analysis were employed to investigate the quasispecies nature of the 5'UTR following extraction of viral RNA from PBMCs and plasma of HCV infected individuals. The nucleotide variation between IRES-derived sequences from PBMCs and plasma indicated the existence of polymorphic sites within the IRES. HCV isolates had divergent variants with unique mutations particularly at positions 107, 204, and 243 of the IRES. Most of the PBMC-derived sequences contained an A-A-A variant at these positions. The mutations associated with the IRESes suggested the presence of unique quasispecies populations in PBMCs compared with plasma.
https://ift.tt/2KhrzSm
Correction: Intervention Strategies into Glycoprotein Hormone Receptors for Modulating (Mal–)function, with Special Emphasis on the TSH Receptor
Horm Metab Res
DOI: 10.1055/a-0789-9317
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Full text
https://ift.tt/2Fxmkz6
CIZ1 Expression Is Upregulated in Hemangioma of the Tongue
Abstract
Hemangioma is a vascular neoplasm and one of the most common benign tumors. The pathogenesis of hemangioma has not been fully understood. CIZ1 (Cip1-interacting zinc finger protein 1) is a nuclear protein and the binding partner of p21. Dysregulation of CIZ1 expression has been reported in various types of cancerous tissues. In this study, we examined CIZ1 expression in hemangioma of the tongue and explored its function in vascular endothelial cells, the proliferative cell type in hemangioma. Immunohistochemistry showed that CIZ1 was highly expressed in hemangioma of the tongue while its expression is minimal in the normal tongue tissues. In vitro, knockdown of CIZ1 expression by shRNA transfection significantly reduced the proliferation and migration of human umbilical vein endothelium cells (HUVECs), suggesting a positive role of CIZ1 in endothelial cell proliferation and migration. Therefore, CIZ1 might involve in pathogenesis of hemangioma of the tongue by regulation of endothelial cell functions.
https://ift.tt/2QVHI29
CCR5 blockage by maraviroc: a potential therapeutic option for metastatic breast cancer
Abstract
Purpose
Bone metastasis is observed in up to 70% of breast cancer patients. The currently available treatment options are palliative in nature. Chemokine receptor 5 (CCR5) has gained attention as therapeutic target in various malignancies. Here, we investigated the effects of targeting CCR5 by its antagonist maraviroc in metastatic breast cancer cells.
Methods
In response to maraviroc exposure, cytotoxicity was assessed using an MTT proliferation assay, whereas the effects on colony formation and migration were assessed using colony formation, transwell chamber migration and scratch wound healing assays, respectively. Apoptosis-related activities were investigated using nuclear staining, annexin-V FITC staining and Western blotting. Cell cycle changes were analysed using flow cytometry and qRT-PCR for cell cycle relevant genes. A nude rat model for breast cancer bone metastasis was used to evaluate the in vivo efficacy of CCR5 targeting by maraviroc. Circulatory levels of the three cognate ligands for CCR5 (CCL3, CCL4, CCL5) were analysed in sera of breast cancer patients using ELISA.
Results
We found that blockade of CCR5 attenuated the proliferation, colony formation and migration of metastatic breast cancer cells, and induced apoptosis and arrest in the G1 phase of the cell cycle. Expression profiling highlighted the involvement of cell cycle related signalling cascades. We also found that treatment with maraviroc significantly inhibited bone metastasis in nude rats implanted with MDA-MB-231 breast cancer cells. Finally, we found that the circulatory levels of three cognate ligands for the CCR5 receptor varied between breast cancer patients and healthy controls.
Conclusion
Our findings indicate that targeting CCR5 may be an effective strategy to combat breast cancer bone metastasis.
https://ift.tt/2zjcGdH
Bridge-to-surgery versus emergency surgery in the management of left-sided acute malignant colorectal obstruction — efficacy, safety and long-term outcomes
Compare efficacy, safety and long-term outcomes of bridge-to-surgery and emergency surgery in acute malignant colorectal obstruction.
https://ift.tt/2r3e93D
Presence of hepatitis B virus markers in umbilical cord blood: exposure to or infection with the virus?
We aimed to clarify whether presence of hepatitis B virus (HBV) markers in cord blood indicates exposure to or infection with HBV.
https://ift.tt/2FxCKrc
Defining the electroclinical phenotype and outcome of PCDH19‐related epilepsy: A multicenter study
Summary
Objective
PCDH19‐related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever‐induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19‐related epilepsy and better define the epileptic phenotype, genotype‐phenotype correlations, and related outcome‐predicting factors.
Methods
We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19‐related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency.
Results
At last follow‐up (median = 12 years, range = 1.9‐42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure‐free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty‐six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124).
Significance
We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long‐term follow‐up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.
https://ift.tt/2qWBaVQ
Identifying symptom clusters among people living with HIV on antiretroviral therapy in China: A network analysis
There exists a research interest shift from separate symptoms to symptom clusters among people living with HIV (PLWH), which may provide a better understanding of symptom management in HIV/AIDS care. However, the symptom clusters among Chinese PLWH is still unknown.
https://ift.tt/2FxBdkW
Preoperative Predictors of Choledocholithiasis in Patients Presenting with Acute Calculous Cholecystitis
Markedly elevated liver chemistries in patients presenting with acute calculous cholecystitis (AC) often prompt an evaluation for concomitant choledocholithiasis (CDL). However, current guidelines directing the workup for CDL fail to address this unique population. The aims of this study are to define the range of presenting lab values and imaging findings in AC, develop a model to predict the presence of concurrent CDL, and develop a management algorithm that can be easily applied on presentation.
https://ift.tt/2DwBnX7
Endoscopic control of polyp burden and expansion of surveillance intervals in serrated polyposis syndrome
Serrated polyposis syndrome (SPS) increases colorectal cancer (CRC) risk. We describe the numbers of colonoscopies and polypectomies performed to achieve and maintain low polyp burdens, and the feasibility of expanding surveillance intervals in patients who achieve endoscopic control.
https://ift.tt/2QadFXp
Different risk factors between early and late cancer recurrences in patients without additional surgery after noncurative endoscopic submucosal dissection for early gastric cancer
Cancer recurrence is observed in some patients without additional radical surgery after endoscopic submucosal dissection (ESD) that does not fulfill the curability criteria for early gastric cancer (EGC), categorized as "noncurative resection" or "curability C-2" in the guidelines. However, time to cancer recurrence is different in such patients. Thus, we aimed to identify the risk factors of early and late cancer recurrences in these patients.
https://ift.tt/2DwrJnj
Continued citation of retracted radiation oncology literature - Do we have a problem?
Retracted literature continues to be cited as legitimate work across many scientific disciplines. This study aimed to quantify the number and characterise the nature of citations of retracted radiation oncology articles occurring after publication of the retraction note. The study found that 92% of the 358 examined post-retraction citations referenced retracted articles as legitimate work.
https://ift.tt/2qVM4uJ
Smoking and Lung Cancer Mortality in the United States From 2015 to 2065 A Comparative Modeling Approach
Background:
Tobacco control efforts implemented in the United States since the 1960s have led to considerable reductions in smoking and smoking-related diseases, including lung cancer. Objective:
To project reductions in tobacco use and lung cancer mortality from 2015 to 2065 due to existing tobacco control efforts. Design:
Comparative modeling approach using 4 simulation models of the natural history of lung cancer that explicitly relate temporal smoking patterns to lung cancer rates. Setting:
U.S. population, 1964 to 2065. Participants:
Adults aged 30 to 84 years. Measurements:
Models were developed using U.S. data on smoking (1964 to 2015) and lung cancer mortality (1969 to 2010). Each model projected lung cancer mortality by smoking status under the assumption that current decreases in smoking would continue into the future (status quo trends). Sensitivity analyses examined optimistic and pessimistic scenarios. Results:
Under the assumption of continued decreases in smoking, age-adjusted lung cancer mortality was projected to decrease by 79% between 2015 and 2065. Concomitantly, and despite the expected growth, aging, and longer life expectancy of the U.S. population, the annual number of lung cancer deaths was projected to decrease from 135 000 to 50 000 (63% reduction). However, 4.4 million deaths from lung cancer are still projected to occur in the United States from 2015 to 2065, with about 20 million adults aged 30 to 84 years continuing to smoke in 2065. Limitation:
Projections assumed no changes to tobacco control efforts in the future and did not explicitly consider the potential effect of lung cancer screening. Conclusion:
Tobacco control efforts implemented since the 1960s will continue to reduce lung cancer rates well into the next half-century. Additional prevention and cessation efforts will be required to sustain and expand these gains to further reduce the lung cancer burden in the United States. Primary Funding Source:
National Cancer Institute.https://ift.tt/2INxH44
Losing Embryos, Finding Justice: Life, Liberty, and the Pursuit of Personhood
The authors discuss the unintentional loss of more than 4000 eggs and embryos from over 950 patients that has precipitated lawsuits raising thorny legal and ethical issues.
https://ift.tt/2qWsJto
https://ift.tt/2qWsJto
Pitfalls and Potential in Medicare's Move Toward Outpatient Care Episodes
Efforts by Medicare to promote value in health care through episode-based bundled payments have largely focused on inpatient care and on procedures. The authors discuss the potential benefits and challenges in efforts to develop programs for episode-based bundled payments for the management of chronic conditions among outpatients.
https://ift.tt/2FFSKro
https://ift.tt/2FFSKro
Intermediate Diabetes Outcomes in Patients Managed by Physicians, Nurse Practitioners, or Physician Assistants A Cohort Study
Background:
Primary care provided by nurse practitioners (NPs) and physician assistants (PAs) has been proposed as a solution to expected workforce shortages. Objective:
To examine potential differences in intermediate diabetes outcomes among patients of physician, NP, and PA primary care providers (PCPs). Design:
Cohort study using data from the U.S. Department of Veterans Affairs (VA) electronic health record. Setting:
568 VA primary care facilities. Patients:
368 481 adult patients with diabetes treated pharmaceutically. Measurements:
The relationship between the profession of the PCP (the provider the patient visited most often in 2012) and both continuous and dichotomous control of hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) was examined on the basis of the mean of measurements in 2013. Inverse probability of PCP type was used to balance cohort characteristics. Hierarchical linear mixed models and logistic regression models were used to analyze continuous and dichotomous outcomes, respectively. Results:
The PCPs were physicians (n = 3487), NPs (n = 1445), and PAs (n = 443) for 74.9%, 18.2%, and 6.9% of patients, respectively. The difference in HbA1c values compared with physicians was −0.05% (95% CI, −0.07% to −0.02%) for NPs and 0.01% (CI, −0.02% to 0.04%) for PAs. For SBP, the difference was −0.08 mm Hg (CI, −0.34 to 0.18 mm Hg) for NPs and 0.02 mm Hg (CI, −0.42 to 0.38 mm Hg) for PAs. For LDL-C, the difference was 0.01 mmol/L (CI, 0.00 to 0.03 mmol/L) (0.57 mg/dL [CI, 0.03 to 1.11 mg/dL]) for NPs and 0.03 mmol/L (CI, 0.01 to 0.05 mmol/L) (1.08 mg/dL [CI, 0.25 to 1.91 mg/dL]) for PAs. None of these differences were clinically significant. Limitation:
Most VA patients are men who receive treatment in a staff-model health care system. Conclusion:
No clinically significant variation was found among the 3 PCP types with regard to diabetes outcomes, suggesting that similar chronic illness outcomes may be achieved by physicians, NPs, and PAs. Primary Funding Source:
VA Health Services Research and Development.https://ift.tt/2qWsGxS
Switching to High-Deductible Health Plans: It Is Going to Be a Bumpy Ride
In this issue, Wharam and colleagues take a useful step in evaluation of high-deductible health insurance plans. The editorialist discusses the findings and the difficulty of determining the value of high-deductible plans, particularly for patients with chronic illness.
https://ift.tt/2FIBHoD
https://ift.tt/2FIBHoD
The Changing Definition of a Primary Care Provider
Jackson and colleagues showed that patients with diabetes who received care from nurse practitioners and physician assistants working within the Veterans Affairs health system had outcomes equivalent to those of patients cared for by physicians in a primary care setting. The editorialist discusses the findings and the importance of team-based care for persons with diabetes.
https://ift.tt/2FFSJUm
https://ift.tt/2FFSJUm
High-Deductible Insurance and Delay in Care for the Macrovascular Complications of Diabetes
Background:
Little is known about the long-term effects of high-deductible insurance on care for chronic medical conditions. Objective:
To determine whether a transition from low-deductible to high-deductible insurance is associated with delayed medical care for macrovascular complications of diabetes. Design:
Observational longitudinal comparison of matched groups. Setting:
A large national health insurer during 2003 to 2012. Participants:
The intervention group comprised 33 957 persons with diabetes who were continuously enrolled in low-deductible (≤$500) insurance plans during a baseline year followed by up to 4 years in high-deductible (≥$1000) plans. The control group included 294 942 persons with diabetes who were enrolled in low-deductible plans contemporaneously with matched intervention group members. Intervention:
Employer-mandated transition to a high-deductible plan. Measurements:
The number of months it took for persons in each study group to seek care for their first major macrovascular symptom, have their first major diagnostic test for macrovascular disease, and have their first major procedure-based treatment was determined. Between-group differences in time to reach a midpoint event rate were then calculated. Results:
No baseline differences were found between groups. During follow-up, the delay for the high-deductible group was 1.5 months (95% CI, 0.8 to 2.3 months) for seeking care for the first major symptom, 1.9 months (CI, 1.4 to 2.3 months) for the first diagnostic test, and 3.1 months (CI, 0.5 to 5.8 months) for the first procedure-based treatment. Limitation:
Health outcomes were not examined. Conclusion:
Among persons with diabetes, mandated enrollment in a high-deductible insurance plan was associated with delays in seeking care for the first major symptoms of macrovascular disease, the first diagnostic test, and the first procedure-based treatment. Primary Funding Source:
National Institute of Diabetes and Digestive and Kidney Diseases.https://ift.tt/2qUv2NC
Firearm Injury Prevention: AFFIRMing That Doctors Are in Our Lane
On 8 November 2018, the National Rifle Association (NRA) took to Twitter to admonish doctors to "stay in their lane." The NRA does not believe firearm-related injury and its prevention is within the purview of physicians. We could not disagree more.
https://ift.tt/2FvROFE
https://ift.tt/2FvROFE
Mechanisms That Contribute to a Profound Reduction of the HIV-1 Reservoir After Allogeneic Stem Cell Transplant
This article has been corrected. The original version (PDF) is appended to this article as a Supplement.
https://ift.tt/2CiZnMP
Background:
The multifactorial mechanisms associated with radical reductions in HIV-1 reservoirs after allogeneic hematopoietic stem cell transplant (allo-HSCT), including a case of HIV cure, are not fully understood. Objective:
To investigate the mechanism of HIV-1 eradication associated with allo-HSCT. Design:
Nested case series within the IciStem observational cohort. Setting:
Multicenter European study. Participants:
6 HIV-infected, antiretroviral-treated participants who survived more than 2 years after allo-HSCT with CCR5 wild-type donor cells. Measurements:
HIV DNA analysis, HIV RNA analysis, and quantitative viral outgrowth assay were performed in blood, and HIV DNA was also measured in lymph nodes, ilea, bone marrow, and cerebrospinal fluid. A humanized mouse model was used for in vivo detection of the replication-competent blood cell reservoir. HIV-specific antibodies were measured in plasma. Results:
Analysis of the viral reservoir showed that 5 of 6 participants had full donor chimera in T cells within the first year after transplant, undetectable proviral HIV DNA in blood and tissue, and undetectable replication-competent virus (<0.006 infectious unit per million cells). The only participant with detectable virus received cord blood stem cells with an antithymocyte globulin–containing conditioning regimen, did not develop graft-versus-host disease, and had delayed complete standard chimerism in T cells (18 months) with mixed ultrasensitive chimera. Adoptive transfer of peripheral CD4+ T cells to immunosuppressed mice resulted in no viral rebound. HIV antibody levels decreased over time, with 1 case of seroreversion. Limitation:
Few participants. Conclusion:
Allo-HSCT resulted in a profound long-term reduction in the HIV reservoir. Such factors as stem cell source, conditioning, and a possible "graft-versus-HIV-reservoir" effect may have contributed. Understanding the mechanisms involved in HIV eradication after allo-HSCT can enable design of new curative strategies. Primary Funding Source:
The Foundation for AIDS Research (amfAR).https://ift.tt/2CiZnMP
On-Demand Sildenafil as a Treatment for Raynaud Phenomenon A Series of n -of-1 Trials
Background:
Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk–benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative. Objective:
To assess the efficacy and safety of on-demand sildenafil in RP. Design:
Series of randomized, double-blind, n-of-1 trials. (ClinicalTrials.gov: NCT02050360) Setting:
Outpatients at a French university hospital. Participants:
Patients with primary or secondary RP. Intervention:
Each trial consisted of a multiple crossover study in a single patient. Repeated blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily. Measurements:
Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy. Results:
38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients. Limitation:
The response to sildenafil was substantially heterogeneous among patients. Conclusion:
Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP. Primary Funding Source:
GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rhône-Alpes (academic funding) and Pfizer.https://ift.tt/2JsuJSQ
Reducing Firearm Injuries and Deaths in the United States: A Position Paper From the American College of Physicians
For more than 20 years, the American College of Physicians (ACP) has advocated for the need to address firearm-related injuries and deaths in the United States. Yet, firearm violence continues to be a public health crisis that requires the nation's immediate attention. The policy recommendations in this paper build on, strengthen, and expand current ACP policies approved by the Board of Regents in April 2014, based on analysis of approaches that the evidence suggests will be effective in reducing deaths and injuries from firearm-related violence.
https://ift.tt/2Jntm7T
San Francisco Voters End the Sale of Flavored Tobacco Products Despite Strong Industry Opposition
In June 2018, voters in San Francisco supported implementation of a law prohibiting the sale of flavored tobacco products, including menthol cigarettes and flavored vaping liquids, despite a $12 million campaign funded almost entirely by the R.J. Reynolds Tobacco Company to oppose the law. This commentary discusses the vote and the public health campaign to support it.
https://ift.tt/2ILJTSF
https://ift.tt/2ILJTSF
Epidermal Growth Factor Receptor Mutation Detection in Cerebrospinal Fluid of Lung Adenocarcinoma Patients with Leptomeningeal Metastasis
Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.
https://ift.tt/2Dx1tsY
Prediction of Subgenome Additive and Interaction Effects in Allohexaploid Wheat
Whole genome duplications have played an important role in the evolution of angiosperms. These events often occur through hybridization between closely related species, resulting in an allopolyploid with multiple subgenomes. With the availability of affordable genotyping and a reference genome to locate markers, breeders of allopolyploids now have the opportunity to manipulate subgenomes independently. This also presents a unique opportunity to investigate epistatic interactions between homeologous orthologs across subgenomes. We present a statistical framework for partitioning genetic variance to the subgenomes of an allopolyploid, predicting breeding values for each subgenome, and determining the importance of intergenomic epistasis. We demonstrate using an allohexaploid wheat breeding population evaluated in Ithaca, NY and an important wheat dataset from CIMMYT previously shown to demonstrate non-additive genetic variance. Subgenome covariance matrices were constructed and used to calculate subgenome interaction covariance matrices for variance component estimation and genomic prediction. We propose a method to extract population structure from all subgenomes at once before covariances are calculated to reduce collinearity between subgenome estimates. Variance parameter estimation was shown to be reliable for additive subgenome effects, but was less reliable for subgenome interaction components. Predictive ability was equivalent to current genomic prediction methods. Including only inter-genomic interactions resulted in the same increase in accuracy as modeling all pairwise marker interactions. Thus, we provide a new tool for breeders of allopolyploid crops to characterize the genetic architecture of existing populations, determine breeding goals, and develop new strategies for selection of additive effects and fixation of inter-genomic epistasis.
https://ift.tt/2FwI9yR
A Low Resolution Epistasis Mapping Approach To Identify Chromosome Arm Interactions in Allohexaploid Wheat
Epistasis is an important contributor to genetic variance. In inbred populations, pairwise epistasis is present as additive by additive interactions. Testing for epistasis presents a multiple testing problem as the pairwise search space for modest numbers of markers is large. Single markers do not necessarily track functional units of interacting chromatin as well as haplotype based methods do. To harness the power of multiple markers while minimizing the number of tests conducted, we present a low resolution test for epistatic interactions across whole chromosome arms. Epistasis covariance matrices were constructed from the additive covariances of individual chromosome arms. These covariances were subsequently used to estimate an epistatic variance parameter while correcting for background additive and epistatic effects. We find significant epistasis for 2% of the interactions tested for four agronomic traits in a winter wheat breeding population. Interactions across homeologous chromosome arms were identified, but were less abundant than other chromosome arm pair interactions. The homeologous chromosome arm pair 4BL/4DL showed a strong negative relationship between additive and interaction effects that may be indicative of functional redundancy. Several chromosome arms appeared to act as hubs in an interaction network, suggesting that they may contain important regulatory factors. The differential patterns of epistasis across different traits demonstrates that detection of epistatic interactions is robust when correcting for background additive and epistatic effects in the population. The low resolution epistasis mapping method presented here identifies important epistatic interactions with a limited number of statistical tests at the cost of low precision.
https://ift.tt/2qTRiHt
Mechanisms of Aerodigestive Symptoms in Infants with Varying Acid Reflux Index Determined by Esophageal Manometry
To test whether symptom generation in infants is related to the severity of gastroesophageal reflux disease (GERD) symptoms as determined by the Acid Reflux Index (ARI), stimulus media, and stimulus volume during provocative esophageal manometry.
https://ift.tt/2QUcNDl
Caution Is Required When Using Non-Food and Drug Administration-Cleared Assays to Diagnose Sexually Transmitted Infections in Children
Nucleic acid amplification testing is the gold-standard for Chlamydia trachomatis and Neisseria gonorrhoeae testing in adults. We present 3 pediatric cases in which testing resulted in probable false-positive results. Clinicians should avoid tests without clearance from a regulatory agency and should maintain consistent communication with laboratories.
https://ift.tt/2PHiKan
Korean Youth with Comorbid Allergic Disease and Obesity Show Heightened Psychological Distress
To explore psychological distress in Korean adolescents having allergic disease comorbid with obesity.
https://ift.tt/2QWNDnR
Pediatric Idiopathic Intervertebral Disc Calcification: Single-Center Series and Review of the Literature
To review pediatric idiopathic intervertebral disc calcification (PIIVDC) within a single center and within the literature to outline the disease course, management, and outcome.
https://ift.tt/2PEblIL
Factors associated with adverse pregnancy outcome in Debre Tabor town, Northwest Ethiopia: a case control study
The aim of this study was to assess the socioeconomic and demographic factors on adverse pregnancy outcomes.
https://ift.tt/2QWOgxJ
The influence of maternal pregnancy glucose concentrations on associations between a fetal imprinted gene allele score and offspring size at birth
Previously we found that certain fetal imprinted genes represented as an allele score are associated with maternal pregnancy glucose concentrations. Recently it was reported that fetal polymorphisms with stron...
https://ift.tt/2PHUhBT
FDA Alerts Health Care Professionals and Patients Not To Use Sterile Drug Products from Pharm D Solutions
Audience: Health Care Professionals; Patients The U.S. Food and Drug Administration is alerting health care professionals and patients not to use drug products intended to be sterile that are produced and distributed by Pharm D Solutions LLC,...
https://ift.tt/2qUthjq
External Beam Radiation Therapy Enhances Mesenchymal Stem Cell–Mediated Sodium–Iodide Symporter Gene Delivery
Human Gene Therapy, Volume 29, Issue 11, Page 1287-1300, November 2018.
https://ift.tt/2OT9Yk7
Preparation of Poly(pentafluorophenyl acrylate) Functionalized SiO2 Beads for Protein Purification
A protocol for the preparation of poly(pentafluorophenyl acrylate) (poly(PFPA)) grafted silica beads is presented. The poly(PFPA) functionalized surface is then immobilized with antibodies and used successfully for the protein separation through immunoprecipitation.
https://ift.tt/2zdj0n6
The Cancer Moonshot: Moving from Planning to Research
Dr. Dinah Singer, co-chair of the Cancer Moonshot Blue Ribbon Panel, provides an update to the cancer community on the science being supported under the Moonshot initiative.
https://ift.tt/2Q3bsx1
Label-Free Identification of Lymphocyte Subtypes Using Three-Dimensional Quantitative Phase Imaging and Machine Learning
We describe a protocol for the label-free identification of lymphocyte subtypes using quantitative phase imaging and a machine learning algorithm. Measurements of 3D refractive index tomograms of lymphocytes present 3D morphological and biochemical information for individual cells, which is then analyzed with a machine-learning algorithm for identification of cell types.
https://ift.tt/2QbyNwk
Opioid Misuse Varies With Sexual Orientation
MONDAY, Nov. 19, 2018 -- Opioid misuse varies with sexual orientation, with increased misuse among female bisexuals, according to a study published online Nov. 19 in the American Journal of Preventive Medicine. Dustin T. Duncan, Sc.D., from the New...
https://ift.tt/2qTpL8X
A case report of pseudo-progression after pembrolizumab in metastatic gastric cancer and a review of immunotherapy in gastroesophageal tumors
Summary
In this report, we present the medical history of a 30-year-old male patient with HER2- and PD-L1-negative metastasized adenocarcinoma of the gastric cardia, who received three cycles of pembrolizumab (200 mg every 2 weeks) after the failure of the first-line (1L) treatment with docetaxel, cisplatin, 5‑fluorouracil (DCF). A restaging computed tomography (CT) scan for the chest and abdomen revealed an apparent progressive disease; therefore, the treatment was terminated. Five months after the termination of the treatment, a new CT scan demonstrated a spontaneous treatment response although no treatment was given during this time period, indicating pseudo-progression of the tumor in the first restaging after three cycles of pembrolizumab. This finding is apparently due to the long-term sustainable immunological effects of pembrolizumab. The current report will present this rare case in more detail and summarize the closed and ongoing clinical trials of immunotherapy drugs in gastroesophageal cancer.
https://ift.tt/2BhqeIh
Educational no. 4: PCR-based methods
Summary
For decades, polymerase chain reaction (PCR) has been playing a fundamental role in hematology. Not only in diagnostics, but also in follow-up and therapeutic decision-making, PCR impacts the treatment of patients with neoplastic diseases. In this educational, commonly used PCR methods are explained. In addition, the strengths and weaknesses of PCR in the clinical setting are illustrated.
https://ift.tt/2KePEZK
HIV Transmission Risk Small With Antiretroviral Compliance
MONDAY, Nov. 19, 2018 -- The risk for sexual transmission of HIV is negligible when an HIV-positive sex partner adheres to antiretroviral therapy and maintains viral suppression, according to research published in the November issue of CMAJ, the...
https://ift.tt/2FvOZ7I
Patient Outcomes Tied to Valve Replacement Volume
MONDAY, Nov. 19, 2018 -- Hospitals with high caseloads of both surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) have the best outcomes, according to a study published online Oct. 31 in JAMA...
https://ift.tt/2qTpMK3
Onset of Musculoskeletal Adverse Events Varies Between Statins
MONDAY, Nov. 19, 2018 -- The onset of musculoskeletal adverse events (MAEs) during statin monotherapy is significantly faster with use of atorvastatin and rosuvastatin versus simvastatin, according to a study published online Nov. 7 in Pharmacology...
https://ift.tt/2FvOPgC
Prevalence of Food Allergy 7.6 Percent in U.S. Children
MONDAY, Nov. 19, 2018 -- The prevalence of food allergy (FA) is 7.6 percent among children in the United States, according to a study published online Nov. 19 in Pediatrics. Ruchi S. Gupta, M.D., M.P.H., from Northwestern University in Chicago, and...
https://ift.tt/2qTpLFZ
ACAAI: Oral Immunotherapy Is Protective in Peanut Allergy
MONDAY, Nov. 19, 2018 -- Patients with peanut allergy who received oral immunotherapy, compared with those who received placebo, were able to ingest higher doses of peanut protein without dose-limiting symptoms, according to a study published online...
https://ift.tt/2FvOY3E
Health Utility Values Improve After Septorhinoplasty
MONDAY, Nov. 19, 2018 -- Patients with nasal airway obstruction have health utility values (HUVs) below the mean Australian norm, with improvement noted after open septorhinoplasty, according to a study published online Nov. 15 in JAMA Facial...
https://ift.tt/2FvOURs
Transcendental Meditation Benefits Veterans With PTSD
MONDAY, Nov. 19, 2018 -- A non-trauma-focused therapy, transcendental meditation (TM), can decrease the severity of posttraumatic stress disorder (PTSD) symptoms among veterans, according to a study published online Nov. 15 in The Lancet...
https://ift.tt/2qVf5Xt
Patient Education Ups VTE Prophylaxis in Hospital Setting
MONDAY, Nov. 19, 2018 -- A patient-centered education bundle intervention can reduce nonadministration of venous thromboembolism (VTE) prophylaxis, according to a study published online Nov. 16 in JAMA Network Open. Elliott R. Haut, M.D., Ph.D.,...
https://ift.tt/2Fy8OLz
MS Relapse Drops During Pregnancy but Rises After
MONDAY, Nov. 19, 2018 -- Rates of multiple sclerosis (MS) relapse decrease during pregnancy but increase postpartum, according to a study published online Oct. 23 in Neurology. Maria K. Houtchens, M.D., from Brigham and Women's Hospital in Boston,...
https://ift.tt/2qSLa2d
Predictive value of lymphocyte-to-monocyte ratio in the preoperative setting for progression of patients with breast cancer
Abstract
Background
The lymphocyte-to-monocyte ratio (LMR) has been used as a parameter reflecting systemic inflammation in several tumors, and is reportedly associated with prognosis in cancer patients. In this study, we evaluated the predictive value of LMR for progression and chemosensitivity in breast cancer patients treated with preoperative chemotherapy.
Methods
LMR was evaluated in 239 patients with breast cancer treated with neoadjuvant chemotherapy (NAC) with 5-fluorouracil, epirubicin, and cyclophosphamide, followed by weekly paclitaxel with or without trastuzumab, and subsequent curative surgery. The correlations between LMR and clinicopathological features, prognosis, and pathological complete response (pCR) rate of NAC were evaluated retrospectively. We also evaluated the predictive value of neutrophil-to-lymphocyte ratio (NLR), and compared the predictive values of LMR and NLR.
Results
We set 6.00 as the cut-off level for LMR based on the receiver operating characteristic (ROC) curve. A total of 119 patients (49.8%) were classified in the high-LMR group and 120 (50.2%) were classified in the low-LMR group. The low-LMR group had significantly worse disease-free survival rate (DFS) in all patients (p = 0.005) and in triple-negative breast cancer patients (p = 0.006). However, there was no significant correlation between LMR and pCR. Multivariate analysis showed that low LMR was an independent risk factor for DFS (p = 0.008, hazard ratio = 2.245). However, there was no significant difference in DFS (p = 0.143, log-rank) between patients in the low- and high-NLR groups.
Conclusions
LMR may be a useful prognostic marker in patients with breast cancer.
https://ift.tt/2QTRTV1
Highly sensitive detection of ALK resistance mutations in plasma using droplet digital PCR
Abstract
Background
On-target resistance mechanisms found in one-third of patients receiving anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are secondary ALK mutations in ALK-rearranged non-small cell lung cancer (NSCLC). There are large variations in the resistant mutations, unlike the epithelial growth factor receptor (EGFR) T790 M seen with the use of EGFR-TKIs. Liquid biopsy approaches using cell-free DNA (cfDNA) are used for screening and monitoring of mutations in NSCLC. However, feasible protocol for the simultaneous detection of multiple secondary ALK mutations using droplet digital PCR (ddPCR) has not been developed. An efficient strategy using cfDNA in cancer diagnostics, the development of more accurate and cost-effective tools to identify informative multiple secondary ALK mutations is clinically required.
Methods
To establish a feasible assay to monitor ALK-TKI resistance mutations, we first evaluated the feasibility of ddPCR-based screening for cfDNA mutation detection of 10 distinct secondary ALK mutations. Positive samples were then re-analyzed using mutation-specific probes to track the growth of mutation clones with a high sensitivity.
Results
Blood samples from seven ALK-positive patients were analyzed using the ddPCR protocol. Secondary G1202R ALK mutations were identified in 2 of 7 patients by the screening assay. Using the mutation-specific probes, monitoring the resistant clone during the clinical course of the disease was well demonstrated in each of the patients.
Conclusion
The protocol for ddPCR-based liquid biopsy has a feasibility for the screening of secondary ALK-TKI resistance mutations and offers a tool for a cost-effective monitoring of progression in NSCLC.
https://ift.tt/2PCC88v
Is right-sided ligamentum teres hepatis always accompanied by left-sided gallbladder? Case reports and literature review
Abstract
Right-sided ligamentum teres (RSLT) hepatis is a rare anatomical variant in which the fetal umbilical vein is connected to the right paramedian trunk of the portal vein. Despite its rarity, it is crucial for surgeons and intervention specialists because of its frequent association with intrahepatic vascular and biliary anomalies. Inattention to these anomalies before intervention, especially living-donor liver transplantation, can have life-threatening consequences. The relationship between gallbladder location and RSLT is still controversial, with RSLT regarded as one of the critical features of left-sided gallbladder in most studies. According to these hypotheses, once RSLT is present, left-sided gallbladder must be found as well. Here, we report three cases in which RSLT was associated with intrahepatic portal vein anomalies. In one case, the gallbladder was left-sided, but in the other two cases, it had a normal cholecystic axis to the right of the umbilical fissure. Therefore, the relationship between RSLT and gallbladder location may require redefinition, and surgeons should be aware of vascular anomalies once RSLT has been detected, even in the absence of left-sided gallbladder or biliary anomalies.
Teaching Points
• Right-sided ligamentum teres (RSLT) hepatis is a rare anatomical variant, which is frequently associated with intrahepatic vascular and biliary anomalies. Previous studies had discussed the vascular anomalies in livers with RSLT.
• However, no predictable correlation exists between portal vein anomalies and anomalous biliary confluences in patients with RSLT. Moreover, we found that RSLT does not always coexist with left-sided gallbladder.
• Unawareness of these vascular and biliary anomalies in liver with RSLT before intervention can have life-threatening consequences.
• Thus, the vascular and biliary variations should be surveyed in multimodality imaging studies such as dynamic CT, 3D magnetic resonance cholangiopancreatography, or digital subtraction angiography once the RSLT is detected before intervention.
https://ift.tt/2TrMplW
Compound kushen injection suppresses human acute myeloid leukaemia by regulating the Prdxs/ROS/Trx1 signalling pathway
Abstract
Background
The increase in the levels of reactive oxygen species (ROS) in acute myeloid leukemia (AML) patients has been previously described; thus, it is important to regulate ROS levels in AML.
Methods
Flow cytometry were used to assess the in vitro effect of compound kushen injection (CKI). Quantitative proteomics were used to analyse the mechanism. The AML patient-derived xenograft (PDX) model were used to evaluate the in vivo effect of CKI.
Results
We found that intracellular ROS levels in AML cells were decreased, the antioxidant capacity were increased when treated with CKI. CKI inhibited the proliferation of AML cells and enhanced the cytotoxicity of AML cells, which has few toxic effects on haematopoietic stem cells (HSCs) and T cells. At the single-cell level, individual AML cells died gradually by CKI treatment on optofluidic chips. CKI promoted apoptosis and arrested cell cycle at G1/G0 phase in U937 cells. Furthermore, higher peroxiredoxin-3 (Prdx3) expression levels were identified in CKI-treated U937 cells through quantitative proteomics detection. Mechanically, the expression of Prdx3 and peroxiredoxin-2 (Prdx2) was up-regulated in CKI-treated AML cells, while thioredoxin 1 (Trx1) was reduced. Laser confocal microscopy showed that the proteins Prdx2 could be Interacted with Trx1 by CKI treatment. In vivo, the survival was longer and the disease was partially alleviated by decreased CD45+ immunophenotyping in peripheral blood in the CKI-treated group in the AML PDX model.
Conclusions
Antioxidant CKI possess better clinical application against AML through the Prdxs/ROS/Trx1 signalling pathway.
https://ift.tt/2BhYjry
Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb
Abstract
Background
Melanoma, the most aggressive form of skin cancer, is characterized by high rates of metastasis, drug resistance and mortality. Here we investigated the role of Semaphorin 5A (Sema5A) on the properties associated with melanoma progression and the factors involved in Sema5A regulation.
Methods
Western blotting, qRT-PCR, Chromatin immunoprecipitation (ChIP) assay, immunohistochemistry of melanoma patient specimens and xenograft tissues, in vitro Transwell assay for cell migration and invasion evaluation, in vitro capillary-like structure formation analysis.
Results
A significant correlation of Sema5A mRNA expression and melanoma progression was observed by analyzing GEO profile dataset. Endogenous Sema5A protein was detected in 95% of human melanoma cell lines tested, in 70% of metastatic specimens from patients affected by melanoma, and 16% of in situ melanoma specimens showed a focal positivity. We demonstrated that Sema5A regulates in vitro cell migration and invasion and the formation of vasculogenic structures. We also found an increase of Sema5A at both mRNA and protein level after forced expression of Bcl-2. By use of transcriptional and proteasome inhibitors, we showed that Bcl-2 increases the stability of Sema5A mRNA and protein. Moreover, by ChIP we demonstrated that Sema5A expression is under the control of the transcription factor c-Myb and that c-Myb recruitment on Sema5A promoter is increased after Bcl-2 overexpression. Finally, a concomitant decrease in the expression of Sema5A, Bcl-2 and c-Myb proteins was observed in melanoma cells after miR-204 overexpression.
Conclusion
Overall our data provide evidences supporting the role of Sema5A in melanoma progression and the involvement of Bcl-2, miR-204 and c-Myb in regulating its expression.
https://ift.tt/2Kf6Azq
Diffuse large B‑cell lymphoma
Summary
Since the introduction of anti-CD20 antibodies and polychemotherapy, diffuse large B‑cell lymphoma (DLBCL) has become a treatable, and, for a high proportion of patients, curable disease. However, a sizeable proportion of patients, especially in poor-prognosis subgroups, will relapse.
The landscape of therapy in DLBCL has seen some exciting changes in the past years, most notably with the introduction of CAR-T-cell therapy. All three major trials were recently updated and showed sustained responses and excellent preliminary survival data.
Other immunotherapies are gaining ground as well, as the antibody–drug conjugate polatuzumab vedotin has shown to be effective in relapsed DLBCL in combination with chemo-immunotherapy (rituximab and bendamustine). Complete remission rates increased from 15 to 40% and overall survival from 4.7 to 11.8 months. Polatuzumab is also being studied in previously untreated patients and results are awaited in 2019.
Checkpoint inhibitors, the mainstay of therapy in a variety of malignancies, are also being studied in DLBCL. Interim results of an ongoing phase I/II study of atezolizumab with R‑CHOP in previously untreated patients show 83% complete remissions in early data.
Other novel substances, like anti-CD47-antibodies and PI3-kinase inhibitors, show promising efficacy in early trials in relapsed patients as well.
https://ift.tt/2A8j86T
Ewing’s Sarcoma of Scapula: a Rare Case Report
Abstract
Neoplasms arising from scapula are rare. We herein, present a rare case of Ewing's sarcoma of scapula in a 9-year-old male child. Extensive literature search reveals that less than 20 similar cases have been reported so far. The index case had been treated with multimodal therapies—chemotherapy, surgery, and radiotherapy. This case is reported to highlight the rarity of the case and discuss the review of literature comprehensively.
https://ift.tt/2Bi0bjW
Comparison of the efficacy and safety of Transarterial chemoembolization with and without Apatinib for the treatment of BCLC stage C hepatocellular carcinoma
Abstract
Background
Hepatocellular carcinoma (HCC) is a common cancer worldwide, with a poor prognosis. Most patients are diagnosed at advanced stages and are only eligible for palliative therapy. Therefore, this study aimed to evaluate the safety and efficacy of transcatheter arterial chemoembolization (TACE) combined with apatinib (TACE-apatinib) treatment and TACE-alone treatment for Barcelona Clinic Liver Cancer stage C HCC.
Methods
We retrospectively reviewed 80 consecutive patients with BCLC stage C HCC who received TACE-apatinib or TACE-alone as the initial treatment. We compared the clinical and laboratory outcomes, imaging findings at 1 and 3 months after TACE, tumor response, time to progression (TTP), overall survival (OS), and adverse events between both groups.
Results
The overall response rate was higher in the TACE-apatinib group than in the TACE-alone group at 1 and 3 months after treatment (66.7% vs 39.6%, respectively, P = 0.020; 45.8% vs 17.6%, respectively, P = 0.021). The median TTP and OS in the TACE-apatinib group were longer than those of the TACE-alone group (TTP: 6.3 months vs 3.5 months, respectively, P = 0.002; OS: 13.0 months vs 9.9 months, respectively, P = 0.041). Apatinib-associated side effects such as hypertension, hand-foot syndrome, oral ulcers, proteinuria, and diarrhea were more prevalent in the TACE-apatinib group than in TACE-alone group (P < 0.05).
Conclusion
Compared to TACE-alone treatment, TACE-apatinib increased the TTP, OS, and tumor-response rate at 1 and 3 months after treatment of BCLC stage C HCC without any significant increase in severe adverse events.
https://ift.tt/2PCqBpJ
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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