Self-Administration of Long-Acting Somatostatin Analogues in NET Patients—Does It Affect the Clinical Outcome?

Background and Objectives: Long-acting somatostatin analogues (SSA) (octreotide LAR and lanreotide Autogel) are recommended as first line treatment of locally advanced or metastatic well-differentiated neuroendocrine tumors (NETs) with a good expression of somatostatin receptor (SSTR). Both of these SSAs are usually administered via injections repeated every 4 weeks. The purpose of the study was to compare the route of SSA administration (injection performed by professional medical staff and self-administration of the drug) with progression-free survival. Materials and methods: 88 patients in 2019 and 96 patients in 2020 with locally advanced or metastatic well-differentiated NETs were included in the study. All patients had a good expression of SSTR type 2 and had been treated for at least 3 months with a stable dose of long-acting somatostatin analogue every 4 weeks. All of them had received training on drug self-injections from professional NET nurses at the beginning of the COVID-19 epidemic. Results: The rate of NET progression in the study group in 2020 was higher than in 2019 29.1% vs. 18.1% (28 vs. 16 cases), p = 0.081. Conclusions: The method of administration of long-acting SSA injection performed by professional medical staff vs. self-injection of the drug may significantly affect the risk of NET progression. The unequivocal confirmation of such a relationship requires further observation.

Identification of miR-20a-5p as Robust Normalizer for Urine microRNA Studies in Renal Cell Carcinoma and A Profile of Dysregulated microRNAs

Renal cell carcinoma (RCC) is the third most frequent urinary malignancy and one of the most lethal. Current diagnostic and follow-up techniques are harmful and unspecific in low-grade tumors. Novel minimally invasive markers such as urine microRNAs (miRNAs) are under study. However, discrepancies arise among studies in part due to lack of consent regarding normalization. We aimed to identify the best miRNA normalizer for RCC studies performed in urine samples together with a miRNA profile with diagnostic value and another for follow-up. We evaluated the performance of 120 candidate miRNAs in the urine of 16 RCC patients and 16 healthy controls by RT-qPCR followed by a stability analysis with RefFinder. In this screening stage, miR-20a-5p arose as the most stably expressed miRNA in RCC and controls, with a good expression level. Its stability was validated in an independent cohort of 51 RCC patients and 32 controls. Using miR-20a-5p as normalizer, we adjusted and validated a diagnostic model for RCC with three miRNAs (miR-200a-3p, miR-34a-5p and miR-365a-3p) (AUC = 0.65; Confidence Interval 95% [0.51, 0.79], p = 0.043). let-7d-5p and miR-205-5p were also upregulated in patients compared to controls. Comparing RCC samples before surgery and fourteen weeks after, we identified let-7d-5p, miR-152-3p, miR-30c-5p, miR-362-3p and miR-30e-3p as potential follow-up profile for RCC. We identified validated targets of most miRNAs in the renal cell carcinoma pathway. This is the first study that identifies a robust normalizer for urine RCC miRNA studies, miR-20a-5p, which may allow the comparison of future studies among laboratories. Once confirmed in a larger independent cohort, the miRNAs profiles identified may improve the non-invasive diagnosis and follow-up of RCC.

Peptide Linker Affecting the Activity Retention Rate of VHH in Immunosorbents

VHH-based immunosorbents are an emerging and promising tool for the removal of toxic substances from plasma. However, the small size of VHHs is a double-edged sword, bringing both benefits and drawbacks to the immunosorbent. The small size of the VHH allows a higher coupling density, while the closer distance to the resin might create steric hindrance for paratope access. The latter could be avoided by inserting a linker between the VHH and the gel attachment site. Here, we report an approach to improve the activity retention of the immobilized VHH by selecting suitable linkers between the VHH and the site-specific immobilization site on the resin. Seven peptide linkers differing in length and flexibility were fused to the VHH and contained the formylglycine generating enzyme (FGE) recognition sequence. These constructs were expressed in the cytoplasm of bacteria and purified, the VHH production yield and affinity for its cognate antigen was measured. Furthermore, the fGly conversion, the immobilization of the aldehyde-containing nanobodies, the immobilization on resin and the antigen binding activity of the VHH-based immunoadsorbents was monitored. The VHH with longer and rigid, proline-rich linkers exhibited good expression yield of approximately 160 mg/L of culture, a fGly conversion of up to 100%, and the highest activity retention rate of more than 68%. This study unveiled two suitable linkers for the preparation of VHH-based immunosorbents that will assist the development of their clinical application.

INVESTMENT DECISION ANALYSIS OF INTERNATIONAL MEGAPROJECTS BASED ON COGNITIVE LINGUISTIC CLOUD MODELS

The investment decision analysis of international megaprojects is a major area of interest. The choice of international megaprojects usually depends on the multi-discipline knowledge from experts. Besides, experts may not be able to provide accurate or crisp evaluations such as deterministic numbers on each criterion because of the complexity of the decision problem. In this case, natural evaluation language, either single linguistic variable or multiple linguistic variables, is a good expression tool for experts to sharing their opinions freely and flexibly. To this end, this paper introduces a cognitive linguistic cloud model for the investment decision analysis of international megaprojects as a decision support system and provides a survey of the cloud model. Afterwards, the technique to tackle multi-granularity of cognitive linguistic information is proposed to capture personalized semantics. In addition, operators of the cognitive linguistic model are proposed to aggregate natural language. The proposed approach has the advantages of more accurate utilization of experts’ knowledge, reducing uncertainties, and more effective operations of cognitive clouds for decision analysis in comparing with the state of the art. Finally, a case study about the investment of international megaprojects is given to show the flexibility and understandability of the cognitive linguistic model.

Identification of miR-29c-3p as a Robust Normalizer for Urine microRNA Studies in Bladder Cancer

Bladder cancer (BC) is among the most frequent malignancies worldwide, being the most expensive cancer to treat and monitor and the most lethal urological cancer. Urine microRNAs (miRNAs) have been proposed as novel non-invasive biomarkers to early diagnose and monitor BC patients in order to avoid the performance of current aggressive diagnostic techniques. However, huge discrepancies arise among studies mainly due to the lack of standardization in the normalization, a crucial step in all miRNA studies. Our aim was to identify the best miRNA normalizer for miRNA studies in urine of BC patients. We evaluated the performance of 110 candidate miRNAs in urine of 35 BC patients and 15 healthy controls by Real Time quantitative Polymerase Chain Reaction (RT-qPCR) followed by a stability analysis with RefFinder. In this screening stage, miR-29c-3p arose as the most stably expressed miRNA in BC and controls, with a good expression level. Stability of miR-29c-3p expression was validated in an independent cohort of 153 BC patients and 57 controls. Finally, we evaluated the robustness of miR-29c-3p as normalizer in the expression study of miR-200c-3p, a potential diagnostic marker for BC. We propose miR-29c-3p as a normalizer for miRNA studies in BC urine. This is the first study that characterizes a reliable normalizer that may allow the comparison of future urine miRNA studies as non-invasive biomarkers for BC diagnosis and monitoring.

Format chain exchange (FORCE) for high-throughput generation of bispecific antibodies in combinatorial binder-format matrices

Generation of bispecific antibodies (bsAbs) requires a combination of compatible binders in formats that support desired functionalities. Here, we report that bsAb-matrices can be generated by Format Chain Exchange (FORCE), enabling screening of combinatorial binder/format spaces. Input molecules for generation of bi/multi-valent bsAbs are monospecific entities similar to knob-into-hole half-antibodies, yet with complementary CH3-interface-modulated and affinity-tagged dummy-chains. These contain mutations that lead to limited interface repulsions without compromising expression or biophysical properties of educts. Mild reduction of combinations of educts triggers spontaneous chain-exchange reactions driven by partially flawed CH3-educt interfaces resolving to perfect complementarity. This generates large bsAb matrices harboring different binders in multiple formats. Benign biophysical properties and good expression yields of educts, combined with simplicity of purification enables process automation. Examples that demonstrate the relevance of screening binder/format combinations are provided as a matrix of bsAbs that simultaneously bind Her1/Her2 and DR5 without encountering binder or format-inflicted interferences.

The use of 18S ribosomal DNA, ITS and rbcL molecular markers to study the genus Dunaliella (Dunaliellaceae) in Iranian samples: A phylogenetic approach

The microalga Dunaliella has been the focus of attention over recent decades owing to its high biotechnological potential for the production of β-carotene, biofuels and even as a good expression system for the production of recombinant proteins. Different species of this genus have unique features, biological characteristics and biotechnological potential. Therefore, it is necessary to have a clear and reliable taxonomic method to identify different species of Dunaliella. Although several taxonomic systems are available for Dunaliella based on morphological, physiological and molecular features, none of these methods are reliable enough and some controversies exist over different classification systems. In the current study, molecular techniques and bioinformatics tools have been used to re-assess the phylogenetic position of Dunaliella species based on 18S ribosomal DNA (18S rDNA), ITS and rbcL regions. The overall findings based on these markers provide a new and more reliable tool for phylogenetic analysis of Dunaliella species/strains.

Crowdfunding for unmet medical needs: the case of CAR-T and Gofundme

Background Crowdfunding (CF) is the practice of financing a project by raising money from a large number of people. Many patients use online CF platforms to fund medical needs, whether unmet by their healthcare service - therefore to be sought elsewhere -, or when unable to afford them. CAR-T (Chimeric antigen receptor T-cells) is an innovative therapy approved to treat several types of lymphoma and with potential to treat many other cancers. CAR-T is available in most countries through clinical trials only and its diffusion is limited by high costs. Gofundme is a CF platform ’leader in online medical fundraising’. The objective of this study is to shed some light on the phenomenon of CF for CAR-T therapy, describing the campaigns started on Gofundme. Methods We extracted data from CAR-T campaigns started in Europe and publicly available on Gofundme until March 2019. Data related to each campaign has been analyzed and reported through descriptive analyses. Results Since 2017, 26 CAR-T treatment campaigns have been started. Due to the privacy policy of the platform, we were able to retrieve data from only 12 of them; 3 campaigns were closed, thus not disclosing enough data to be included. Nine campaigns were studied: 4 from Italy, 4 from the UK, 1 from Spain. The United States were the main destination. The median campaign goal was 180k€. The number of campaign shares on social media and the percentage of goal raised seemed to be linked. Conclusions CF is unquestionably a good expression of the Internet: it channels empathy towards important causes, providing tangible help. However, when applied to healthcare - especially to experimental treatments -, several questions arise. Patients affected by treatment resistant cancers may be prone trying new treatments to keep the hope alive, even when indication is missing or scientific evidence is lacking. Policymakers should monitor healthcare related CF campaigns, both for equity and safety reasons. Key messages Policymaker should monitor healthcare related CF campaigns, both for equity and safety reasons. Healthcare related crowdfunding campaigns could be interpreted as an indicator of unmet medical needs.

Tipologi Ayat Ahl Al-Kitab Dalam Al-Qur’an

In the Qur'an the discussion of the Ahl al-Kitab there are many categories. Some contain a condemnation of the Ahl al-book, some of which contain a good expression to the Ahl al-Kitab. What becomes an allergy is that if a person only emphasizes one aspect of the community but the fact that he or she is even crashing into another. A person who only emphasizes the religious community and does not care about other maslahah such as the benefit of the soul (Hifz an-nafs) and common sense (Hifz al-' Aql) will cause various problems in the midst of society. The results concluded that there were five fundamental benefits in the verses relating to the Ahl al-Kitab. Whether it is religious, mental, resourceful, hereditary, or treasure. Then when traced deeper and comparably, there is a relation between one maslahah and other maslahah, such as the recommendation to do justice to the Ahl al-book which was originally an attempt of the Hifz al-'aql turns positive impact For the benefit of the soul (Hifz al-Nafs) and religious benefits (Hifz ad-Din), this is what is then referred to as Maslahah interconnectivity.

Calculation of absorbed dose due to the 90Y-DOTATOC peptide receptor radionuclide therapy by MCNP5/X

Strong beta emitters, like 90Y, 177Lu labelled peptide, are used for treatment of neuroendocrine tumours where there is a good expression of somatostatin receptors. In this work, MCNP5/X computer software and ORNL human phantoms were used to calculate absorbed dose due to 90Y labelled DOTATOC in the peptide receptor radionuclide therapy. Tumour was considered as a sources of beta radiation and represented as a sphere with diameter of 1-4 cm and 5 cm in liver, pancreas, and lungs. Results are expressed as absorbed dose per unit of cumulated activity, S ? value in units mGy?(MBq?s)?1. The far largest dose is in tumour itself, then in organ which contains the tumour. Doses in other organs, where the metastasis are the most frequent, due to the bremsstrahlung radiation, are much smaller and could be neglected. The largest dose, 8.66?10?3 mGy?(MBq?s)?1 was obtained for tumour with size of 3 cm.