Current oscillations in Vanadium Dioxide: evidence for electrically triggered percolation avalanches

In this work, we experimentally and theoretically explore voltage controlled oscillations occurring in micro-beams of vanadium dioxide. These oscillations are a result of the reversible insulator to metal phase transition in vanadium dioxide. Examining the structure of the observed oscillations in detail, we propose a modified percolative-avalanche model which allows for voltage-triggering. This model captures the periodicity and waveshape of the oscillations as well as several other key features. Importantly, our modeling shows that while temperature plays a critical role in the vanadium dioxide phase transition, electrically induced heating cannot act as the primary instigator of the oscillations in this configuration. This realization leads us to identify electric field as the most likely candidate for driving the phase transition

Risk factors of occupation related back pain and neck pain among patients attending tertiary care hospital, Ahmedabad, India

Introduction: Neck/back pain is one of the common health problems associated with significant impact on health resulting in sickness absenteeism. Neck/back pain is one of important causes of disability adjusted life years worldwide. The Objectives of study were: To identify various occupations related risk factors and their possible role in occurrence of back pain/neck pain and Visual analogue scale(VAS) assessment of their perceived pain. Methods: The study was conducted at one of the tertiary care hospital at Ahmedabad city, India. All patients above age of 18 years attending physiotherapy department for treatment of back pain/neck pain and gave consent were taken as study participants. Information about certain body postures in their lifestyle or at workplace which can have effects on back pain/neck pain were asked. VAS for perceived pain was anchored by “no pain” (score 0) and “pain as bad as it could be” (score 100). Data were entered in MS Excel and analyzed by frequency, contingency coefficient and Goodman & Kruskal’s Gamma test. Result and Conclusion: Total of 512 participants were included in study, among which 53 & 392 participants had Neck pain and Back pain alone, respectively, while 67 participants had both Neck and Back pain. Age, Marital status, socioeconomic class, BMI and type of occupation revealed statistically significant association with severity of pain. Various body postures like prolonged sitting/ standing, frequent bending at waist/knee, Pulling/Pushing heavy objects, frequent weight lifting > 10 kg. and repetitive movement of back/neck revealed as statistically significant risk factors for back/neck pain

DIVERSIFICATION OF PYRROLIZIDINE ALKALOIDS AS PLANT DEFENCE COMPOUNDS AND THEIR EFFECT ON Spodoptera exigua CELL LINES

Pyrrolizidine alkaloids (PAs) are part of the constitutive chemical defence against herbivores. PA composition in plants is strongly determined by the environment, mostly in an unpredictable way. In this study the ability of different Jacobaea tissue cultures types including shoot, root and complete plants to produce and diversify PAs was evaluated. Jacobaea vulgaris, Jacobaea aquatica and three hybrids of a cross were used representing different genotypes. The cultures were harvested after nine weeks and PA content was measured using LC-MS/MS. We observed that not only roots, as known so far, but also shoots were able to synthesise de-novo PAs. Significant differences in total concentration of PAs were observed with the lowest concentration in the roots, followed by shoots and the highest concentration in complete plants. Evaluation of PA composition showed that senecionine- and otosenine-like PAs were present in both roots and shoots while next to senecionine-like PAs, jacobine- and erucifoline-like PAs occurred in the shoots and complete plants. Among these PAs, jacobine and erucifoline are the most effective against insect herbivores as indicated by correlative studies. In this way, the above-ground plants that suffer from herbivore attack are better defended. To test this, the two PAs and other commercially available senecionine­like PAs including, senecionine, seneciphylline, retrorsine, and senkirkine were tested as free base and N-oxide forms. A range of concentrations from 0 70 ppm was added to Spodoptera exigua cell line. The result showed jacobine and erucifoline appeared to be the most toxic PAs proving their major role in plant defence against generalist herbivores. Senkirkine and seneciphylline showed a lower toxicity than jacobine and erucifoline but higher than retrorsine. Senecionine was not toxic at the tested concentrations. In all toxic PAs the free base form was more toxic than the N-oxide form. The results obtained give us an insight in what plant organs PAs are produced and how there are distributed over different plant organs, that have great relevance to understand their role in plant defense.Keywords: Jacobaea, Spodoptera exigua, pyrrolizidine alkaloids, diversification, toxicity

Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies

Optimum efficacy is the primary goal for any cancer therapy, and entails controlling tumour growth and prolonging survival as far as possible. The prognosis for patients with metastatic renal cell carcinoma (mRCC) has greatly improved with the introduction of targeted therapies. This review examines the development and efficacy of targeted agents for the management of mRCC, the challenges offered by their rapid emergence, and discusses how mRCC treatment may evolve in the future. Improvements in progression-free survival and overall survival rates, observed with targeted agents, indicate that it may now be possible to change mRCC from a rapidly fatal and largely untreatable condition into a chronic disease. The major challenges to further advances in targeted therapy for mRCC include overcoming drug resistance, identifying the most effective sequence or combination of targeted agents, optimising clinical trial design and managing the cost of treatment

Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials

A subset of patients with metastatic renal cell carcinoma treated with sunitinib achieved long-term response (ie, progression-free survival [PFS] > 18 months). Long-term responders had improved objective response rate, PFS, and overall survival versus others. Patient baseline characteristics predictive of long-term response to sunitinib were identified. Background: We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months. Patients and Methods: A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤ 18 months (“others”). PFS and overall survival (OS) were summarized using Kaplan–Meier methodology. Results: Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P <.0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan (67.1% vs. 51.2%; P =.0018) and greater median maximum on-study tumor shrinkage from baseline (−56.9 vs. −27.1; P <.0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase ≤ 1.5 upper limit of normal (ULN), corrected calcium ≤ 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index ≥ 25 kg/m2, and low neutrophil-to-lymphocyte ratio were associated with LTR. Conclusion: A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS

First-line treatment of metastatic clear cell renal cell carcinoma: a decision-making analysis among experts

Background: The treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has been transformed by targeted therapies with tyrosine kinase inhibitors (TKI) and more recently by the incorporation of immune checkpoint inhibitors (ICI). Today, a spectrum of single agent TKI to TKI/ICI and ICI/ICI combinations can be considered and the choice of the best regimen is complex. Materials and methods: We performed an updated decision-making analysis among 11 international kidney cancer experts. Each expert provided their treatment strategy and relevant decision criteria in the first line treatment of mccRCC. After the collection of all input a list of unified decision criteria was determined and compatible decision trees were created. We used a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees, to determine the most common treatment recommendations as well as deviations. Results: Diverse parameters were considered relevant for treatment selection, various drugs and drug combinations were recommended by the experts. The parameters, chosen by the experts, were performance status, International Metastatic renal cell carcinoma Database Consortium (IMDC) risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. The systemic therapies selected for first line treatment were sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib. Conclusion: A wide spectrum of treatment recommendations based on multiple decision criteria was demonstrated. Significant inter-expert variations were observed. This demonstrates how data from randomized trials are implemented differently when transferred into daily practice

Soluble Isoforms of Vascular Endothelial Growth Factor Are Predictors of Response to Sunitinib in Metastatic Renal Cell Carcinomas

Angiogenesis is the target of several agents in the treatment of malignancies, including renal cell carcinoma (RCC). There is a real need for surrogate biomarkers that can predict selection of patients who may benefit from antiangiogenic therapies, prediction of disease outcome and which may improve the knowledge regarding mechanism of action of these treatments. Tyrosine kinase inhibitors (TKI) have proven efficacy in metastatic RCC (mRCC). However, the molecular mechanisms underlying the clinical response to these drugs remain unclear.The present study aimed to identify molecular biomarkers associated with the response to sunitinib, a Tyrosine kinase inhibitor. To evaluate this relationship, primary tumors from 23 metastatic RCC patients treated by sunitinib were analyzed for a panel of 16 biomarkers involved in tumor pathways targeted by sunitinib, using real-time quantitative reverse-transcriptase PCR. Nine of the 23 patients (39%) responded to sunitinib. Among transcripts analyzed, only the levels of vascular endothelial growth factor (VEGF) soluble isoforms (VEGF(121) and VEGF(165)) were associated with the response to sunitinib (P = 0.04 for both). Furthermore, the ratio of VEGF soluble isoforms (VEGF(121)/VEGF(165)) was significantly associated with prognosis (P = 0.02).This preliminary study provides a promising tool that might help in the management of metastatic RCC, and could be extended to other tumors treated by TKI

Metastatic collecting duct carcinoma of the kidney treated with sunitinib

Collecting duct carcinoma (CDC) of the kidney is a rare and aggressive malignant tumor arising from the distal collecting tubules which has been shown to have a poor response to several kinds of systemic therapy. We present a case of metastatic CDC that responded favorably to a multiple tyrosine kinase inhibitor, sunitinib, achieving a partial response in both lung and skeletal metastases. To our knowledge, this is the first report showing therapeutic activity of sunitinib against CDC. Considering these findings, it would be worthwhile prospectively investigating the role of multiple tyrosine kinase inhibitors, particularly sunitinib, in the management of metastatic CDC