We will prove that when uniformly distributed random numbers are sorted by value, their successive differences are a exponentially distributed random variable Ex(λ). For a set of n random numbers, the parameters of mathematical expectation and standard deviation is λ =n−1. The theorem was verified on four series of 200 sets of 101 random numbers each. The first series was obtained on the basis of decimals of the constant e=2.718281…, the second on the decimals of the constant π =3.141592…, the third on a Pseudo Random Number generated from Excel function RAND, and the fourth series of True Random Number generated from atmospheric noise. The obtained results confirm the application of the derived theorem in practice.

Molecular tweezers (MTs) are supramolecular host molecules equipped with two aromatic pincers linked together by a spacer (Gakh, 2018). They are endowed with fascinating properties originating from their ability to hold guests between their aromatic pincers (Chen and Whitlock, 1978; Zimmerman, 1991; Harmata, 2004). MTs are finding an increasing number of medicinal applications, e.g., as bis-intercalators for DNA such as the anticancer drug Ditercalinium (Gao et al., 1991), drug activity reverters such as the bisglycoluril tweezers Calabadion 1 (Ma et al., 2012) as well as radioimmuno detectors such as Venus flytrap clusters (Paxton et al., 1991). We recently embarked on a program to create water-soluble tweezers which selectively bind the side chains of lysine and arginine inside their cavity. This unique recognition mode is enabled by a torus-shaped, polycyclic framework, which is equipped with two hydrophilic phosphate groups. Cationic amino acid residues are bound by the synergistic effect of disperse, hydrophobic, and electrostatic interactions in a kinetically fast reversible process. Interactions of the same kind play a key role in numerous protein-protein interactions, as well as in pathologic protein aggregation. Therefore, these particular MTs show a high potential to disrupt such events, and indeed inhibit misfolding and self-assembly of amyloidogenic polypeptides without toxic side effects. The mini-review provides insight into the unique binding mode of MTs both toward peptides and aggregating proteins. It presents the synthesis of the lead compound CLR01 and its control, CLR03. Different biophysical experiments are explained which elucidate and help to better understand their mechanism of action. Specifically, we show how toxic aggregates of oligomeric and fibrillar protein species are dissolved and redirected to form amorphous, benign assemblies. Importantly, these new chemical tools are shown to be essentially non-toxic in vivo. Due to their reversible moderately tight binding, these agents are not protein-, but rather process-specific, which suggests a broad range of applications in protein misfolding events. Thus, MTs are highly promising candidates for disease-modifying therapy in early stages of neurodegenerative diseases. This is an outstanding example in the evolution of supramolecular concepts toward biological application.

Abstract Background In 2017 a new PN led clinic was established for immunotherapy patients. At the 1-year mark to ensure patients were satisfied with the service provision, a patient experience survey was conducted. The survey explored if patients felt comfortable in discussing side effects with the PN and if they felt part of their treatment related decisions. Importantly patients were asked if they had confidence and trust in the PN. Methods The survey was provided to all patients whom attended the PN led clinic from May 2017 to May 2018. The survey consisted of 10 closed questions using the Likert scale, with spaces provided for personal comments. Data collection period was 1.06.18 to 29.06.18. Estimated number of patients was 10. Results Questionnaires were provided to a total of 10 patients. Three questionnaires could not be provided to 3 patients whom attended the PN led clinic as they had died. Two patients did not respond back. 6/8 patients strongly agreed (SAg) to feeling comfortable in discussing treatment related side effects and 2/8 patients agreed (Ag). This same result was found when patients were asked if they felt involved in the decisions related to their care e.g. stopping immunotherapy treatment at 2 yrs. With respect to having confidence and trust with the advice and care provided by the PN, 7 patients SAg and 1 Ag. All patients felt that they were being listened to and had the opportunity to ask questions during their consultations (7 patients SAg and 1 Ag). Reassuringly all 8 patients said that they would recommend this service to their friends and family (7 patients SAg and 1 Ag). Conclusions This survey was to ensure patients were satisfied with being reviewed by a PN and as the service was new to the melanoma unit in 2017; it was vital that the patients had the opportunity to evaluate the service provision. With this positive feedback the clinic was expanded from September 2018 and to date 36 patients have now been seen within the PN led immunotherapy clinic and another patient experience survey is due. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Abstract Background Intratumour heterogeneity is recognised across different tumour types and has implications for therapeutic resistance. At present, clinical practice often relies upon molecular information derived from a single biopsy of a primary or metastatic tumour. This information guides treatment choice but may not be representative of the diversity of the tumour. It is currently difficult to evaluate how effectively a single region guides treatment decisions because the formalin-fixed residual surgical sample that is not paraffin embedded for diagnostic purposes is typically thrown away. Retention and homogenisation – ‘blending’- of this residual formalin-fixed leftover tumour tissue creates a more representative sample for analysis. DNA may be extracted from this sample for sequencing. Pilot data in kidney cancer has demonstrated the potential of this methodology for robust mutational calling, accurate determination of cancer cell fraction and the ability to discern clonal from subclonal variants. Such information may be clinically relevant; for example, discerning resistant subclones prior to treatment, or identifying clonal neoantigens worth targeting with immunotherapy. Trial design In order to establish the feasibility of homogenization as a potential companion diagnostic tool, our study aims to 1) identify the proportion of primary tumour cases that have left over tissue amenable to homogenization across multiple tumour types and 2) pilot homogenization across multiple tumour types. The molecular profile of the homogenate will be compared to that obtained from the diagnostic specimen using next generation sequencing techniques. This is a prospective non-interventional study (NCT03832062). Patients undergoing surgical intervention at The Royal Marsden Hospital (NHS Foundation Trust) with leftover tumour tissue from primary breast, colorectal, gastric, pancreatic, ovarian, renal cancer and sarcoma surgeries, as well as melanoma lymph node dissections will be included in the feasibility assessment. We plan to homogenise 500 cases across different tumour types. The study opened in September 2018 and is expected to run for 2 years. Clinical trial identification NCT03832062; Release date: February 2019. Legal entity responsible for the study Royal Marsden NHS Foundation Trust. Funding Ventana Medical Systems (a subsidiary of Roche). Disclosure L. Gallegos: Full / Part-time employment: Roche. S. Hill: Full / Part-time employment: Roche. A. Barhoumi: Full / Part-time employment: Roche. S. Stanislaw: Full / Part-time employment: Roche. M. Mendoza: Full / Part-time employment: Roche. J.M.G. Larkin: Research grant / Funding (institution): Roche; Advisory / Consultancy: Roche. N. Alexander: Full / Part-time employment: Roche; Shareholder / Stockholder / Stock options: Roche. S. Turajlic: Research grant / Funding (institution): Ventana Medical Systems (subsidiary of Roche). All other authors have declared no conflicts of interest.

Abstract Background ADATPeR is the first prospective study evaluating the role of anti-PD1 agents in the neoadjuvant setting prior to cytoreductive nephrectomy in treatment-naive patients with metastatic clear cell renal cell carcinoma (mccRCC). We performed multi-omic analyses to resolve spatial heterogeneity and temporal dynamics in putative biomarkers of response to anti-PD1 blockade. Methods In a single center study, patients received nivolumab (3mg/kg every 2 weeks) pre- and post-operatively until progressive disease (PD). Primary endpoint was safety, secondary endpoints were response evaluation and exploratory biomarker analysis. Multiregion tumour biopsies were obtained at baseline, on-treatment (week 9) and at PD. Whole-exome sequencing was performed to infer somatic mutations and predict candidate neoantigens (NAs). Tumour immune microenvironment was evaluated using a RNA-seq-derived immune signature and by stromal and intraepithelial tumour infiltrating lymphocytes (TILs) assessments. Results 15 patients were treated. At median follow-up of 12.5 months(m), nivolumab had an acceptable side-effect profile. Overall response rate was 37%. Preliminary transcriptome analyses of pre-treatment biopsies (33 samples from 14 patients; up to 4 regions per case) revealed enrichment for primary-resistance (defined as PD within 2m; n = 4) with immune ‘cold’ tumours, distinct from ’hot’ tumours. Histologic TILs scoring showed concordant immune phenotypic clusters. Primary-resistant cases demonstrated 0% on-treatment stromal- and IE-TILs (2 evaluable patients). In contrast, we observed heavy on-treatment stromal TILs (70-90%) and intraepithelial TILs (30-90%) across 7 regions at nephrectomy in an exceptional responder receiving ongoing treatment (>24 cycles). Conclusions ADATPeR is the first neoadjuvant immune checkpoint inhibitor study pre-cytoreductive nephrectomy, and incorporated multi-omic analyses of putative biomarkers. Baseline immune gene expression signature is distinct in responders compared with non-responders. On-treatment intraepithelial TILs were prominent in those deriving durable clinical benefit. Integrative analyses are ongoing. Clinical trial identification NCT02446860. Legal entity responsible for the study The authors. Funding Bristol-Myers Squibb; The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research; Cancer Research UK (CRUK). Disclosure All authors have declared no conflicts of interest.

In this paper, a stochastic simulation procedure for energy assessment of PV systems is developed and tested. The method is especially adequate for urban applications since the impact of surrounding obstacles both for direct and diffuse irradiance is taken into account. The main input is the system location along with its monthly average irradiance and temperature statistics. Based on the input data, the program generates a set of random years represented by hourly sequences of global horizontal irradiance and ambient temperature. The generated sequences are then converted into the module plane-of-array irradiance and module temperature time series and, consequently, the AC energy production is estimated for each simulated year. The final results are presented in a form of probability density function of the system annual energy output.

In modern market it is very important to deliver products to customers fast. That delivery can be on site or to customer's homes. In order to achieve that it is important to have enough goods stored in warehouses and prepared for delivery. It is not a good decision to clutter up warehouses with the goods because space is limited and expensive and it makes it more complicated to collect orders. Those are the reasons why it is important that number of stored goods converge to the exact number of product units that will be ordered in the future. Demand forecasting tries to solve that problem. In this work demand forecasting algorithm based on Long Short-Term Memory recurrent neural network is described and compared with demand forecasting algorithms developed by authors before.

A number of industrial wireless technologies have emerged over the last decade, promising to replace the need for wires in a variety of use cases. Except for customized time division multiple access (TDMA)-based wireless technologies that can achieve ultralow latency over a very limited area, wireless communication generally has reliability and latency issues when it comes to industrial applications. Closed loop communication requires high reliability (over 99%), limited jitter and latency, which poses a challenge especially over a wide area measuring in hundreds of meters. Extended coverage is promised with the advent of sub-GHz technologies, one of them being IEEE 802.11ah which is the only one that offers sufficient data rate for frequent bidirectional communication. Thus, we evaluated IEEE 802.11ah for low-latency time-critical control loops. We propose the network setup for adjusting the network dynamics to that of control loops, enabling limited jitter and high reliability. We explore the scalability of IEEE 802.11ah network hosting both control loops and monitoring sensors that periodically transmit measurements. Assigning the control loop end-nodes to dedicated restricted access window (RAW) slot results in over 99.99% successful deliveries. Furthermore, interpacket delay is concentrated around the cycle-time in the following or preceding beacon interval in case the beacon interval is at least half the value of the shortest cycle-time. Adjusting the beacon interval to the fastest control loop in the network ensures latency requirements at the cost of maximum achievable throughput and energy consumption.