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Abstract: The cationic amphiphilic antimicrobial peptide gramicidin S (GS) is an effective antibiotic. Its applicability is however restricted to topical infections due to its hemolytic activity. In this study, the process of GS induced hemolysis was investigated in detail for the first time. The morphological changes of red blood cells (RBCs) inflicted by GS were visualized and explained in terms of a physical model. The observed fast rupture events were further investigated with giant unilamellar vesicles (GUVs) as model systems for RBCs. Measurements of membrane fluctuations in GUVs revealed that the membrane surface tension was increased after incubation with GS. These findings are in agreement with the hypothesis that amphiphilic peptides induce membrane rupture by an increase in membrane tension. [Copyright &y& Elsevier]

A letter to the editor is presented describing a case of hyperkeratosis of the scalp and multifocal squamous cell carcinoma in a 74-year-old man.

Background: Mixed adenoneuroendocrine carcinomas are highly malignant tumors with both adenocarcinomatous and neuroendocrine components. They can originate in any organ but are more common in the rectum. Due to their rarity, current treatment recommendations for mixed adenoneuroendocrine carcinoma are based on limited data and follow general guidelines for the management of adenocarcinomas and neuroendocrine neoplasms. Uncertainty regarding the efficacy of the available local and systemic treatment strategies is a compounding issue. Even those patients with locally limited disease have a relatively short life expectancy. In this report, we describe a case of deep rectal mixed adenoneuroendocrine carcinoma with long survival after chemoradiation.Case Presentation: A 48-year-old Caucasian woman was diagnosed with a grade 3 rectal adenocarcinoma combined with a poorly differentiated large cell neuroendocrine carcinoma component and synchronous metastases (cT3cN1cM1) in both lobes of the liver in 2012. She received concomitant chemoradiotherapy followed by four additional cycles of cisplatin plus irinotecan. Initial treatment induced complete remission of the rectal tumor and liver metastases. Consequently, it was not necessary to surgically resect the primary tumor or any of the metastases. Three months after the end of treatment, one metastasis in the first segment of the liver showed regrowth, and stereotactic body radiotherapy of the metastasis and chemotherapy resulted in a clinical complete response. The patient has been recurrence-free for more than 5 years.Conclusions: Extended long-term control of a poorly differentiated metastatic (stage IV) mixed adenoneuroendocrine carcinoma is rare. The multimodal first- and second-line regimens of radiotherapy and chemotherapy described in this case report represent a new therapeutic approach. Encouraged by the results in this case, we compiled a review of the literature on mixed adenoneuroendocrine carcinoma. [ABSTRACT FROM AUTHOR]

Purpose There is a sound theoretical basis but little clinical evidence substantiating the benefits of concurrent chemoradiotherapy with two-drug chemotherapy for locally advanced soft tissue sarcomas. Our five-year data on the feasibility and effectiveness of neoadjuvant chemoradiotherapy with systemically effective doses of adriamycin and ifosfamide combined is presented here. Patients and methods Between 2000 and 2011, 53 patients with UICC (2010) stage I ( n = 1, 1.9%), II ( n = 12, 22.7%) or III ( n = 40, 75.5%) nonmetastatic soft tissue sarcoma received neoadjuvant chemoradiotherapy with ifosfamide (1.5 g/m 2 /day, d1–5, q28) and doxorubicin (50 mg/m 2 /day, d3, q28) plus concurrent radiotherapy with a target dose of 50–64 Gy (median 60 Gy). The treatment of 34 patients (64.2%) was combined with hyperthermia. Results At five years, the local control rate was 89.9% (± 5.7%), distant metastasis-free survival 66.6% (± 7.6%), and survival 83.3% (± 6%). The R0 resection rate was 81.1%. Radiotherapy was completed as planned in all patients and chemotherapy in 42/53 (70.2%). Grades III ( n = 21, 29.6%) and IV ( n = 18, 34%) leukopenia was the main acute adverse event. All acute and chronic non-hematologic toxicities were moderate. Conclusion Neoadjuvant chemoradiotherapy for soft tissue sarcoma is associated with good feasibility, manageable acute and late toxicities, and high local efficacy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel approaches are needed to selectively target mutant forms of EGFR. • Design of a homemade virtual library starting from flavone skeleton. • Three-track virtual screening identified mutant-selective hits. • Synthesis and testing of selected hits in an activity-based enzyme assay. • Nitroflavone scaffold shows selectivity for the EGFR mutants over the wild type one. The inhibition of the Epidermal Growth Factor (EGFR) represents one of the most promising strategies in non-small cell lung cancer (NSCLC) therapy. The recently identified C797S mutation causes resistance of EGFRL858R/T790M against osimertinib, the latest approved third generation EGFR inhibitor. The identification of small molecules capable of selectively inhibiting the T790M mutations also in the late-onset C797S mutation is a desirable strategy and novel chemical structures might provide new insight in the overcoming resistance mechanisms. Here we report the identification of a novel mutant-selective privileged molecular core; guided by a structure-based drug design, a flavone skeleton has been rationally modified, and a virtual library generated. Reversible EGFR inhibitors targeting both L858R/T790M and L858R/T790M/C797S mutations with a higher affinity with respect to the wild type one are discovered via a three-track virtual screening. Selected hits were synthesized and tested in an activity-based enzyme assay against wild-type EGFR, L858R/T790M, as well as L858R/T790M/C797S. The results showed that a nitroflavone-based compound inhibits the phosphorylation of EGFR mutants at low-micromolar concentration showing selectivity over the wild type ones. Structurally similar flavone analogues have been synthesized and the following inhibition assays underlied the importance of both the presence and position of the nitrophenoxy moiety. [ABSTRACT FROM AUTHOR]

Objective The treatment of trigeminal neuralgia is challenging with respect to a sufficient outcome. Medication still represents the basic therapy. If a neurovascular compression syndrome is diagnosed with high resolution MRI more than 80% of the patients undergoing surgery based on microvascular decompression are free of pain in a ten year period as shown in one of our previous follow-up studies. In addition to that, percutaneous treatment options such as thermo-coagulation of the Gasserian ganglion can be effective but are affected with a higher recurrence rate and cannot be used in all cases. Therefore, we started selecting patients with intractable, therapy-resistant trigeminal neuralgia for stereotactic radiosurgery of the trigeminal nerve. Preliminary results of this approach are presented in this study. Methods From 2012 to 2014 eight patients suffering from intractable trigeminal neuralgia underwent linear accelerator-based stereotactic radiosurgery with a Novalis system after fixing a stereotactic frame to the patient’s head under local anesthesia. For the treatment, doses ranging from 60 Gy to 70 Gy were used in a target located at the pontine trigeminal root entry zone of the trigeminal nerve. 80% of the dosage was calculated at a 4mm iso-center. We treated 4 male and 4 female patients (average age 68 years). 4 patients suffered from left-sided and 4 patients from right-sided trigeminal neuralgia. V2 and V3 were the most affected branches. All patients had a history of facial pain for several years with two patients suffering from multiple sclerosis-related trigeminal neuralgia. In all cases, two, three or even four different drugs were used with increasing side effects. For none of the patients, neurovascular compression syndrome was found with MRI. One patient, however, underwent surgery with microvascular decompression. Three patients underwent thermo-coagulation of the Gasserian ganglion once or twice without a lasting effect on facial pain. Four patients had to take a permanent anticoagulation because of pre-existing conditions so that no invasive treatment option could be used. Results Taking into account the follow-up time between 2 years and 1 month, all eight patients had benefit from stereotactic radiosurgery treatment: two patients are completely free of pain without any medication, two patients are free of pain with substantially reduced medication and four patients showed relevant improvement of facial pain including their usual medication or even with reduced medication. In consequence, all patients reported considerably reduced side effects of medication and a relevant improvement in their quality of life. Concerning the side effects of radiosurgery, only one patient developed a facial hypoesthesia. Presumably, this was related to a previous prophylactic brain radiation due to lung cancer. General symptoms such as headache or dizziness were mild and lasted for a short time only. Conclusions The use of linear accelerator-based stereotactic radiosurgery is a safe and effective therapeutic option even for the treatment of intractable and so far therapy-resistant trigeminal neuralgia. It significantly reduces the use of medication and improves the quality of life. In order to prove the adequate long-term control of facial pain further follow-up examinations are necessary with a higher number of patients. However, our preliminary results are encouraging and demonstrate effectiveness in cases where all other treatment options failed. [ABSTRACT FROM AUTHOR]