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Background: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, themedian PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm(HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC. [ABSTRACT FROM AUTHOR]

BACKGROUND Thyroid cancer is the most common malignant endocrine cancer worldwide. The diagnosis and distinction between benign and malignant thyroid neoplasm, especially in follicular patterned thyroid lesions is still difficult. Of the various immuno histochemical markers, Galectin-3 was most reliable in diagnosis of thyroid carcinoma. AIM To study diagnostic utility of Galectin-3 in thyroid neoplasm. METHODS This was laboratory based diagnostic study, where 92 cases of thyroid neoplasm (48-malignant and 44 benign) were analyzed for Galectin-3 expression. The Galectin-3 staining was quantitatively evaluated as percentage of positive tumor cells and qualitatively for intensity of staining. When membrane ± cytoplasmic immunoreactivity of Galectin-3 was present in more than 10% of tumor cells was considered as positive staining. RESULTS Galectin 3 expression was significantly higher in thyroid cancer as compared to benign thyroid neoplasm (p<0.001). 33/35 cases of PTC were positive for Galectin-3 expression. Galectin-3 expression was significantly higher in FTC as compared to FA (p <0.01). Galectin-3 was also useful to differentiate between FVPTC and FTC (p<0.01) and FVPTC from other benign neoplasm (<0.01).The sensitivity, specificity, positive predictive value and negative predictive value in differentiating benign and malignant thyroid neoplasm were 83.33%, 100%,100%, 84.62% respectively. CONCLUSION Galectin-3 is a potential marker in differentiating benign and malignant thyroid neoplasm. It can used as sole marker for differentiating PTC and benign thyroid neoplasm and also useful to differentiate between FVPTC and FTC. [ABSTRACT FROM AUTHOR]

The problems of the North–South Transport Corridor development are directly interrelated with the integration of the regional infrastructure of the countries participating in this project. The importance of this corridor currently affects not only the economic sphere, but also the geopolitics of the world community as a whole, as the power balancing issues in the world economy are engaged. Based on the results of the statistical data study from open sources, the analysis of extensive periodical literature, the pros and cons of the North–South Multimodal Transport Corridor (MTC) project are substantiated, and the promising ways of implementing and improving its effectiveness are identified. Political pressure on a number of participating countries and an asymmetry of interests are highlighted as factors that hinder the active implementation of the project (the most interested participants are Iran and Russia, other parties may have negative geopolitical and economic consequences from participating in the project). There are major challenges concerning the infrastructure development and the insufficient degree of harmonization of the institutional conditions within which the transport corridor operates. On the other hand, the greatest advantages of the North–South Transport Corridor are reducing dependence on other transport routes, including those passing through competitive countries, increasing national security and sovereignty of Russia, consolidating Eurasian integration, improving foreign policy links with the countries in Asia and Africa. In order to maximize the potential of the North–South MTC and increase its competitiveness in comparison with other transport hubs, the following ways are proposed: 1. One-time solution to a set of tasks: modernization of infrastructure, primarily, port infrastructure in Russia, railway infrastructure in Iran; full digitalization of the transport and logistics sphere in all the participating countries; harmonization of institutional conditions for the project implementation in the domain of legislation, customs procedures, business processes, management. 2. More active use of free economic zones and special economic zones. 3. Formation of a special supranational organizational structure that will directly deal with the development of the North– South International Transport Corridor.

The paradigm of the Next Generation cellular network (6G) and beyond is machine-type communications (MTCs), where numerous Internet of Things (IoT) devices operate autonomously without human intervention over wireless channels. IoT's autonomous and energy-intensive characteristics highlight effective energy efficiency (EEE) as a crucial key performance indicator (KPI) of 6G. However, there is a lack of investigation on the EEE of random arrival traffic, which is the underlying platform for MTCs. In this work, we explore the distinct characteristics of F -composite fading channels, which specify the combined impact of multipath fading and shadowing. Furthermore, we evaluate the EEE over such fading under a finite blocklength regime and QoS constraints where IoT applications generate constant and sporadic traffic. We consider a point-to-point buffer-aided communication system model, where (1) an uplink transmission under a finite blocklength regime is examined; (2) we make realistic assumptions regarding the perfect channel state information (CSI) available at the receiver, and the channel is characterized by the F -composite fading model; and (3) due to its effectiveness and tractability, application data are found to have an average arrival rate calculated using Markovian sources models. To this end, we derive an exact closed-form expression for outage probability and the effective rate, which provides an accurate approximation for our analysis. Moreover, we determine the arrival and required service rates that satisfy the QoS constraints by applying effective bandwidth and capacity theories. The EEE is shown to be quasiconcave, with a trade-off between the transmit power and the rate for maximising the EEE. Measuring the impact of transmission power or rate individually is quite complex, but this complexity is further intensified when both variables are considered simultaneously. Thus, we formulate power allocation (PA) and rate allocation (RA) optimisation problems individually and jointly to maximise the EEE under a QoS constraint and solve such a problem numerically through a particle swarm optimization (PSO) algorithm. Finally, we examine the EEE performance in the context of line-of-sight and shadowing parameters. [ABSTRACT FROM AUTHOR]

Metastatic lung neuroendocrine carcinomas provide diagnostic challenges in identifying the cell of origin. High level calcitonin expression is not pathognomonic for medullary thyroid cancer. Tumor mutation analysis may provide essential clues regarding tissue origin and treatment targets. Oncogenic RET gene fusions have been identified in non-small cell lung cancer and non- medullary thyroid cancers, whereas RET point mutations are the key genetic finding in both inherited and sporadic MTC. Patients who receive radiation for the treatment of other cancers have an increased risk of developing a second malignancy, including a neuroendocrine carcinoma. Herein, we present a case of calcitonin-rich neuroendocrine carcinoma emerging on a background of prior radiation and chemotherapy for the treatment of Hodgkin's disease. Identification of a RET gene rearrangement (KIF5B-RET) led to initial successful treatment with selpercatinib, with eventual resistance associated with an activating mutation involving the MEK1 protein (MAP2K1 p. E102-I103 del) that led to relapse and progression of the disease. [ABSTRACT FROM AUTHOR]

BackgroundNintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC).DesignEORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety.ResultsRAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9–6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0–5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42–0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2–not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3–4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9–8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0–5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16–1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1–24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1–NR) in the placebo arm. Grade 3–4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo.ConclusionThis study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.

Simple Summary: The usefulness of calcitonin measurement in fine needle aspiration (FNA-CT) for the diagnosis of medullary thyroid carcinoma (MTC) has been confirmed by several authors. During the review process of records of our patients with thyroid nodules (TNs) and elevated serum CT, we focused our attention on 11 patients with TNs showing at histology thyroid neoplasms other than MTC, as compared with a MTC patients' group. We showed that a high FNA-CT concentration is not only found in MTC but may also be observed in benign/malignant TNs coexisting with diffuse C-cells hyperplasia (CCH) due to contamination of the needle through the CCH area. Since diffuse CCH may cause false positive FNA-CT results, we propose a cautious use of FNA-CT in patients with TNs with increased serum CT and high FNA-CT values to avoid unnecessary surgery. Purpose: The FNA-CT is useful for the diagnosis of MTC. The aim of this study was to evaluate the performance of FNA-CT in TNs coexisting with CCH. Methods: This study retrospectively reviewed the records of 11 patients with TNs submitted to thyroidectomy on the basis of elevated basal and/or stimulated serum CT values, which at histology were not confirmed to be MTC. The results obtained in this group were compared with those of a previously reported group of histologically proven MTC patients submitted to an identical presurgical evaluation. All patients, negative for known mutations in the RET proto-oncogene, were preoperatively submitted to neck ultrasound, FNA-cytology, and FNA-CT. Results: Approximately 6 of 11 patients showed increased (>36 ng/mL, as established in previous studies not involving patients with CCH) FNA-CT. All these patients showed diffuse CCH at histology in the thyroid lobe submitted to FNA; 5 of them were benign at histology, while only one was malignant (papillary thyroid carcinoma, PTC). The remaining 5 of 11 patients had low FNA-CT (<36 ng/mL), and all of them showed only focal CCH in the lobe submitted to FNA; three of them were malignant (2 PTC, 1 follicular carcinoma), while two were benign. Conclusions: Employing the currently proposed cut-off values, false-positive FNA-CT results may be observed in benign/malignant TNs with coexisting diffuse CCH. FNA-CT must therefore be cautiously used in the diagnostic approach for patients with TNs and a slightly increased basal or stimulated serum CT concentration in order to avoid unnecessary surgery. [ABSTRACT FROM AUTHOR]

The authors analyze the forms of interaction between the United States and Latin America in the military sphere. The relevance of studying this issue is due to the aggravation of relations between the collective West and Russia, as well as between the United States and China, within the framework of which Latin America acts as a zone of competition between the world powers. In this regard, the analysis of Latin American vector of US policy in the military aspect from the point of view of Russia’s strategic interests is particularly important. The lack of domestic scientific research on this problem greatly adds to its relevance. As for the novelty, based on the review of the world market of arms and military equipment (AME), this article determines the dynamics and the share of the American producer in the total volume of arms trade. In the context of military-technical cooperation (MTC), the authors also consider the peculiarities of the American military power projection on Latin America, which is a zone of exclusive interests of the United States. Among the key formats of interaction and projection of influence, the authors include the following: arms and military-technical supplies to the armies and security services of the states of the region; training of military personnel in Latin American countries; financing of armies and military units; cooperation programs to optimize the managerial and organizational functions of the Latin American armed forces, establishment and maintenance of various types of military bases, conducting joint military exercises. Using new factual material, we examine each of the listed forms and show the systematic and geostrategic nature of the US influence on the Latin American region in the military aspect. As for military trade, the authors identify the main partners of the United States in South America.

Metastatic lung neuroendocrine carcinomas provide diagnostic challenges in identifying the cell of origin. High level calcitonin expression is not pathognomonic for medullary thyroid cancer. Tumor mutation analysis may provide essential clues regarding tissue origin and treatment targets. Oncogenic RET gene fusions have been identified in non-small cell lung cancer and non-medullary thyroid cancers, whereas RET point mutations are the key genetic finding in both inherited and sporadic MTC. Patients who receive radiation for the treatment of other cancers have an increased risk of developing a second malignancy, including a neuroendocrine carcinoma. Herein, we present a case of calcitonin-rich neuroendocrine carcinoma emerging on a background of prior radiation and chemotherapy for the treatment of Hodgkin’s disease. Identification of a RET gene rearrangement (KIF5B-RET) led to initial successful treatment with selpercatinib, with eventual resistance associated with an activating mutation involving the MEK1 protein (MAP2K1 p. E102-I103 del) that led to relapse and progression of the disease.

The paradigm of the Next Generation cellular network (6G) and beyond is machine-type communications (MTCs), where numerous Internet of Things (IoT) devices operate autonomously without human intervention over wireless channels. IoT’s autonomous and energy-intensive characteristics highlight effective energy efficiency (EEE) as a crucial key performance indicator (KPI) of 6G. However, there is a lack of investigation on the EEE of random arrival traffic, which is the underlying platform for MTCs. In this work, we explore the distinct characteristics of F-composite fading channels, which specify the combined impact of multipath fading and shadowing. Furthermore, we evaluate the EEE over such fading under a finite blocklength regime and QoS constraints where IoT applications generate constant and sporadic traffic. We consider a point-to-point buffer-aided communication system model, where (1) an uplink transmission under a finite blocklength regime is examined; (2) we make realistic assumptions regarding the perfect channel state information (CSI) available at the receiver, and the channel is characterized by the F-composite fading model; and (3) due to its effectiveness and tractability, application data are found to have an average arrival rate calculated using Markovian sources models. To this end, we derive an exact closed-form expression for outage probability and the effective rate, which provides an accurate approximation for our analysis. Moreover, we determine the arrival and required service rates that satisfy the QoS constraints by applying effective bandwidth and capacity theories. The EEE is shown to be quasiconcave, with a trade-off between the transmit power and the rate for maximising the EEE. Measuring the impact of transmission power or rate individually is quite complex, but this complexity is further intensified when both variables are considered simultaneously. Thus, we formulate power allocation (PA) and rate allocation (RA) optimisation problems individually and jointly to maximise the EEE under a QoS constraint and solve such a problem numerically through a particle swarm optimization (PSO) algorithm. Finally, we examine the EEE performance in the context of line-of-sight and shadowing parameters.

ABSTRACT Microbial volatile metabolite 2-methylisoborneol (2-MIB) causes odor and taste issues in drinking water, making it unappealing for human consumption. It has been suggested that 2-MIB biosynthesis consists of two main steps, namely, methylation of geranyl diphosphate into 2-methyl geranyl diphosphate by geranyl diphosphate methyl transferase (GPPMT) and subsequent cyclization into 2-MIB by 2-MIB synthase (MIBS). Pseudanabaena foetida var. intermedia is a 2-MIB-producing cyanobacterium whose GPPMT and MIBS enzymes are encoded by adjacent mtf and mtc genes. The present study identified a 2-MIB-related gene cluster composed of cnbA, mtf, mtc, and cnbB genes in P. foetida var. intermedia. The two homologous cyclic nucleotide-binding protein genes, cnbA and cnbB, were detected adjacent to the mtf and mtc genes, respectively. The nucleotide sequence of the cnbA-mtf-mtc-cnbB gene cluster showed 99.55% identity with 2-MIB synthesis-associated gene cluster of Pseudanabaena sp. dqh15. RT-PCR results revealed that mtf and mtc genes are co-expressed, while cnbA and cnbB genes are expressed independently in P. foetida var. intermedia. To investigate whether only mtf and mtc genes are sufficient for 2-MIB synthesis, the two-gene unit (mtf-mtc) was introduced into Escherichia coli strain JM109 via overexpression vector pYS1C. Gas chromatograph-mass spectrometry results showed that the E. coli strain transformed with mtf-mtc was able to produce 2-MIB. The intracellular 2-MIB level in P. foetida var. intermedia was higher than the extracellular 2-MIB level, while the transformed E. coli strain showed an opposite trend. Growth inhibition was observed in the 2-MIB-producing transformed E. coli strain. IMPORTANCE Contamination of drinking water with odiferous microbial metabolite 2-MIB is a worldwide concern. Removal of 2-MIB from drinking water burdens the water purification process. Therefore, it is important to search for alternative methods, such as suppressing the production of 2-MIB by aquatic microorganisms. For that, it is necessary to expand the current knowledge about the mechanism of 2-MIB synthesis at the genetic level. This study revealed that mtf and mtc genes of the 2-MIB-related gene cluster are transcribed as a single unit in P. foetida var. intermedia, and the expression of both mtf and mtc genes is essential and sufficient for 2-MIB synthesis in E. coli heterologous gene expression system.

Medullary thyroid carcinoma (MTC) arises from parafollicular cells in the thyroid gland, and although rare, it represents an aggressive type of thyroid cancer. MTC is recognized for its low mutational burden, with point mutations in RET or RAS genes being the most common oncogenic events. MTC can be resistant to cytotoxic chemotherapy, and multitarget kinase inhibitors (MKIs) have been considered a treatment option. They act by inhibiting the activities of specific tyrosine kinase receptors involved in tumor growth and angiogenesis. Several tyrosine kinase inhibitors are approved in the treatment of advanced MTC, including vandetanib and cabozantinib. However, due to the significant number of adverse events, debatable efficiency and resistance, there is a need for novel RET-specific TKIs. Newer RET-specific TKIs are expected to overcome previous limitations and improve patient outcomes. Herein, we aim to review MTC signaling pathways, the most recent options for treatment and the applications for personalized medicine. [ABSTRACT FROM AUTHOR]

In order to optimize elevated kidney retention of previously reported minigastrin derivatives, we substituted (R)-DOTAGA by DOTA in (R)-DOTAGA-rhCCK-16/-18. CCK-2R-mediated internalization and affinity of the new compounds were determined using AR42J cells. Biodistribution and µSPECT/CT imaging studies at 1 and 24 h p.i. were carried out in AR42J tumor-bearing CB17-SCID mice. Both DOTA-containing minigastrin analogs exhibited 3- to 5-fold better IC50 values than their (R)-DOTAGA-counterparts. natLu-labeled peptides revealed higher CCK-2R affinity than their natGa-labeled analogs. In vivo, tumor uptake at 24 h p.i. of the most affine compound, [19F]F-[177Lu]Lu-DOTA-rhCCK-18, was 1.5- and 13-fold higher compared to its (R)-DOTAGA derivative and the reference compound, [177Lu]Lu-DOTA-PP-F11N, respectively. However, activity levels in the kidneys were elevated as well. At 1 h p.i., tumor and kidney accumulation of [19F]F-[177Lu]Lu-DOTA-rhCCK-18 and [18F]F-[natLu]Lu-DOTA-rhCCK-18 was high. We could demonstrate that the choice of chelators and radiometals has a significant impact on CCK-2R affinity and thus tumor uptake of minigastrin analogs. While elevated kidney retention of [19F]F-[177Lu]Lu-DOTA-rhCCK-18 has to be further addressed with regard to radioligand therapy, its radiohybrid analog, [18F]F-[natLu]Lu-DOTA-rhCCK-18, might be ideal for positron emission tomography (PET) imaging due to its high tumor accumulation at 1 h p.i. and the attractive physical properties of fluorine-18. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3–METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239–580 of METTL3). We find that METTL3a is required for the METTL3–WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3–METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a–mTOR axis as a potential therapeutic target for breast cancer.

Introduction: MEN 2B syndrome is distinguished by the occurrence of medullary thyroid cancer, pheochromocytoma, mucosal neuromas, marfanoid features, and skeletal anomalies, including kyphoscoliosis, joint laxity, pes cavus, and, in a smaller number of cases, slipped capital femoral epiphysis (SCFE). Case report: We describe a case report of a 15-years-old patient with the diagnosis of the MEN2B syndrome with a rare manifestation of Slipped Capital Femoral Epiphysis (SCFE). A 15-year-old female presented to the orthopedics out-patient department (OPD) with complaints of pain around the right hip and knee and walking with a limp for approximately four months. Additionally, the feeling of enlarged thyroid gland was reported. X-ray confirmed the presence of the SCFE, while thyroid biopsy revealed the presence of medullary thyroid cancer (MTC). Thus, the diagnosis of MEN2B was made. Conclusion: Slipped capital femoral epiphysis (SCFE) can occasionally be a manifestation of MEN 2B syndrome. It is important for physicians to be aware of this association, as it can contribute to the early detection of a potentially life-threatening condition.

N6-methyladenosine (m6A), the most abundant mRNA modification, is deposited in mammals/insects/plants by m6A methyltransferase complexes (MTC) comprising a catalytic subunit and at least five additional proteins. The yeast MTC is critical for meiosis and was known to comprise three proteins, of which two were conserved. We uncover three novel MTC components (Kar4/Ygl036w-Vir1/Dyn2). All MTC subunits, except for Dyn2, are essential for m6A deposition and have corresponding mammalian MTC orthologues. Unlike the mammalian bipartite MTC, the yeast MTC is unipartite, yet multifunctional. The mRNA interacting module, comprising Ime4, Mum2, Vir1, and Kar4, exerts the MTC’s m6A-independent function, while Slz1 enables the MTC catalytic function in m6A deposition. Both functions are critical for meiotic progression. Kar4 also has a mechanistically separate role from the MTC during mating. The yeast MTC constituents play distinguishable m6A-dependent, MTC-dependent, and MTC-independent functions, highlighting their complexity and paving the path towards dissecting multi-layered MTC functions in mammals.

With the rapid development of the internet of things (IoT), the application of machine type communication (MTC) in life has grown substantially, and the deployment of machine type devices (MTD) has become more and more intensive.In this case, if there is an unexpected situation such as a power outage and a network failure, a large-scale MTD will initiate access to the base station at the same time when the device is powered on.When the device accesses the base station, it needs to complete the downlink synchronization, system message receiving, random access (RA) and other processes.However, the preamble resources that can be allocated by the base station are limited and cannot meet such a huge access demand, which causes network congestion and affects the access probability and access delay of the device.In order to alleviate the access conflict of RA, a dynamic random access occasion (RO) adjustment scheme was proposed based on the uplink and downlink subframes and physical random access channel (PRACH) configuration, and time-based part of the MTD with high delay requirements allocates specific preamble resources.The simulation results show that this scheme can effectively improve the throughput of the system and reduce the access delay of the device.

“Machine-to-machine (M2M) is a kind of application and service based on intelligent interaction and networking among machine terminals, which is also called machine-type communications (MTC)”. Here, this paper intends to develop an enhanced secure MTC in LTE Network that takes place under two phases namely, (i) coarse grained attack detection system and (ii) fine grained attack detection system. Initially, the clustering of nodes takes place using LEACH approach and followed by that cluster head (CH) selection takes place by considering the constraints like distance, penalty, energy, and delay. The penalty determined may ensure the secured CH selection results from optimized Neural Network (NN) model. If penalty is assigned as one, particular node is forbidden, which cannot be selected as head node (simply dropped from network). Nodes information is transmitted in Blocks of block chain to authenticate the nodes with the support of Cluster Head (CH) and to ensure the integrity of the block chain. Further, fine grained attack detection system is carried out that authenticate the selected CH to assure attack free network. As a major contribution, the training of NN is carried out by means of a novel algorithm named as Whale with Tri-level Update (WTU). Finally, the superiority of the adopted scheme is analyzed over existing schemes in terms of correlation.

Abstract Background To evaluate the diagnostic value of American College of Radiology (ACR) score and ACR Thyroid Imaging Report and Data System (TI-RADS) for benign nodules, medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) through comparing with Kwak TI-RADS. Methods Five hundred nine patients diagnosed with PTC, MTC or benign thyroid nodules were included and classified into the benign thyroid nodules group (n = 264), the PTC group (n = 189) and the MTC group (n = 56). The area under the curve (AUC) values were analyzed and the receiver operator characteristic (ROC) curves were drawn to compare the diagnostic efficiencies of ACR score, ACR TI-RADS and KWAK TI-RADS on benign thyroid nodules, MTC and PTC. Results The AUC values of ACR score, ACR TI-RADS and Kwak TI-RADS for distinguishing malignant nodules from benign nodules were 0.914 (95%CI: 0.886–0.937), 0.871 (95%CI: 0.839–0.899) and 0.885 (95%CI: 0.854–0.911), respectively. In distinguishing of patients with MTC from PTC, the AUC values of ACR score, ACR TI-RADS and Kwak TI-RADS were 0.650 (95%CI: 0.565–0.734), 0.596 (95%CI: 0.527–0.664), and 0.613 (95%CI: 0.545–0.681), respectively. The AUC values of ACR score, ACR TI-RADS and Kwak TI-RADS for the discrimination of patients with MTC, PTC or benign nodules from patients without MTC, PTC or benign nodules were 0.899 (95%CI: 0.882–0.915), 0.865 (95%CI: 0.846–0.885), and 0.873 (95%CI: 0.854–0.893), respectively. Conclusion The ACR score performed the best, followed ex aequo by the ACR and Kwak TI-RADS in discriminating patients with malignant nodules from benign nodules and patients with MTC from PTC.

Abstract Purpose Marital status has emerged as an important influence on several cancer outcomes, but its role in medullary thyroid cancer (MTC) remains unclear. This study was to explore the effects of marital status on the prognosis of MTC patients and to determine whether its effects vary by age. Patients and methods We retrospectively extracted 1344 eligible patients diagnosed with MTC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Based on the marital status, we divided those patients into married and unmarried groups. We compared the difference in overall survival (OS) and cancer‐specific survival (CSS) between married and unmarried via the Kaplan–Meier analysis. Univariate and multivariate Cox proportional models were performed to identify the prognostic factors of OS and CSS. Results There were 1344 MTC eligible patients in a total of which 883 (65.7%) were married and 461 (34.3%) were unmarried. The comparison observed between married and unmarried patients was as follows: male (45.2% vs. 28.0%), age (≥52 years) (55.9% vs. 44.6%), White (86.7% vs. 78.7%), and undergo surgery (97.7% vs. 93.3%). Multivariate analysis revealed unmarried status as a risk factor independently associated with worse OS (HR: 2.15, 95% CI: 1.59–2.92) rate and CSS (HR: 1.70, 95% CI: 1.17–2.47) rate. In a further analysis stratified by age, there was no significant difference in OS and CSS between married and unmarried patients younger than 52 years. For the remaining group with 52 years old and higher, unmarried patients showed significantly higher risk of OS and CSS than married patients at all stages of the pathology except M1 stage. Conclusion Married patients with MTC have a better prognosis than unmarried ones. Age can affect the association between marital status and the survival of MTC, and married elders may benefit more than youngers.

A new control method for the determination of the malting barley susceptibility to gushing was developed. The method is based on the modified Carlsberg test (MCT) after prior stimulation of barley with substances that promote the germination process. Barleys from the harvest of 2020 and malts produced from them were used to develop and verify the method. The selection of barleys was based on the results of gushing potential detected in the produced malts. To optimise and verify the method, the barley variety Sunshine with a high gushing potential of both barley (139±33 g) and malt (144±13 g), and the barley variety Pionier with zero gushing potential of both barley and malt were used. Malt was produced from the Lodestar barley variety with a high content of the mycotoxin deoxynivalenol. Gushing of the malt was 127±10 g. The gushing potential in barley was determined by the MCT method after prior stimulation of germination. For comparison, the gushing potential was also determined by the MCT method without stimulation of germination. It was proved that stimulation of germination is a key process for correct determination of the susceptibility of barley to gushing. The newly developed method was used for the determination of the gushing potential of five barleys from the harvests of 2020 and 2021. Control gushing determination of five malt samples was performed using the MCT method. An agreement between the measured data was found.

This paper describes the prototype and tests carried out to demonstrate the feasibility of implementing 4G/5G systems based on mobile network operators (MNOs) to transmit signalling critical data for railway systems as part of a possible solution for the Future Railway Mobile Communication System (FRMCS). This communication system design is performed from a protocol-stack perspective, introducing the KPIs for the physical layer (RSRP, RSRQ and SINR), network layer (latency and jitter) and application layer (signalling communication timeout). The analysis focuses on the characterisation of signalling critical railway data to assess the data traffic behaviour in a telecommunications laboratory. Finally, the study validates the approach in a realistic railway environment. [ABSTRACT FROM AUTHOR]

Blood iron levels play a vital role in oxygen metabolism and energy generation whilst transporter protein, transferrin, binds and delivers iron to the transferrin receptor of endosomal compartments of cells. Consequently, the iron-binding capacity of transferrin is an important indicator for many diseases, and its measurements are used in the diagnosis and treatment of anaemias. Various assays, including Total Iron Binding Capacity (TIBC), Unsaturated Iron-Binding Capacity (UIBC) and Transferrin Saturation (TS), were developed to assess the iron-binding capacity of transferrin. Clinically, UIBC is measured in serum by a multi-step liquid ferrozine method and subjected to interference from conditions such as haemolysis and lipemia. Here, we report a quick method that directly measures the concentration of apotransferrin in EDTA-treated plasma, theoretically equivalent to UIBC. Importantly, this supramolecular assembly-based method is more time-efficient, cost-effective and insensitive to serum cation fluctuations. With additional colorimetric property, this method also provides a visual indicator for abnormal health conditions with extreme transferrin statuses such as those found in cancers. Its minimal requirement for equipment would be particularly useful for diagnosis in remote and under-developed regions. [ABSTRACT FROM AUTHOR]

"Machine-to-machine (M2M) is a kind of application and service based on intelligent interaction and networking among machine terminals, which is also called machine-type communications (MTC)". Here, this paper intends to develop an enhanced secure MTC in LTE Network that takes place under two phases namely, (i) coarse grained attack detection system and (ii) fine grained attack detection system. Initially, the clustering of nodes takes place using LEACH approach and followed by that cluster head (CH) selection takes place by considering the constraints like distance, penalty, energy, and delay. The penalty determined may ensure the secured CH selection results from optimized Neural Network (NN) model. If penalty is assigned as one, particular node is forbidden, which cannot be selected as head node (simply dropped from network). Nodes information is transmitted in Blocks of block chain to authenticate the nodes with the support of Cluster Head (CH) and to ensure the integrity of the block chain. Further, fine grained attack detection system is carried out that authenticate the selected CH to assure attack free network. As a major contribution, the training of NN is carried out by means of a novel algorithm named as Whale with Tri-level Update (WTU). Finally, the superiority of the adopted scheme is analyzed over existing schemes in terms of correlation. [ABSTRACT FROM AUTHOR]

Abstract Background A thymoma with chest pain and multilocular thymic cysts (MTCs) is very rare. Case presentation A 49-year-old man presented to another hospital complaining of an anterior chest pain. Chest computed tomography (CT) showed an anterior mediastinal tumor 60 × 30 × 55 mm in size. The boundary with the pericardium or left brachiocephalic vein seemed to be partially unclear while enhanced by the contrast medium, and so the tumor could have invaded them. No definitive diagnosis of myasthenia gravis was made although the serum anti-acetylcholine receptor antibody count was high. We performed an extended thymectomy with combined partial resection of left brachiocephalic vein, left upper lobe, and left phrenic nerve. He was discharged with no chest pain and no complications post-surgery. The tumor was pathologically type B2 thymoma with hemorrhage necrosis and MTCs, and we diagnosed Masaoka stage II because of no histological infiltration to the organs. Conclusions We speculated that hemorrhagic necrosis due to infarction in tumor caused the inflammation to spread to the surrounding organs, which was related to the chest pain and the development of MTCs.

In order to optimize elevated kidney retention of previously reported minigastrin derivatives, we substituted (R)-DOTAGA by DOTA in (R)-DOTAGA-rhCCK-16/-18. CCK-2R-mediated internalization and affinity of the new compounds were determined using AR42J cells. Biodistribution and µSPECT/CT imaging studies at 1 and 24 h p.i. were carried out in AR42J tumor-bearing CB17-SCID mice. Both DOTA-containing minigastrin analogs exhibited 3- to 5-fold better IC50 values than their (R)-DOTAGA-counterparts. natLu-labeled peptides revealed higher CCK-2R affinity than their natGa-labeled analogs. In vivo, tumor uptake at 24 h p.i. of the most affine compound, [19F]F-[177Lu]Lu-DOTA-rhCCK-18, was 1.5- and 13-fold higher compared to its (R)-DOTAGA derivative and the reference compound, [177Lu]Lu-DOTA-PP-F11N, respectively. However, activity levels in the kidneys were elevated as well. At 1 h p.i., tumor and kidney accumulation of [19F]F-[177Lu]Lu-DOTA-rhCCK-18 and [18F]F-[natLu]Lu-DOTA-rhCCK-18 was high. We could demonstrate that the choice of chelators and radiometals has a significant impact on CCK-2R affinity and thus tumor uptake of minigastrin analogs. While elevated kidney retention of [19F]F-[177Lu]Lu-DOTA-rhCCK-18 has to be further addressed with regard to radioligand therapy, its radiohybrid analog, [18F]F-[natLu]Lu-DOTA-rhCCK-18, might be ideal for positron emission tomography (PET) imaging due to its high tumor accumulation at 1 h p.i. and the attractive physical properties of fluorine-18.

Background: To evaluate the diagnostic value of American College of Radiology (ACR) score and ACR Thyroid Imaging Report and Data System (TI-RADS) for benign nodules, medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) through comparing with Kwak TI-RADS. Methods: Five hundred nine patients diagnosed with PTC, MTC or benign thyroid nodules were included and classified into the benign thyroid nodules group (n = 264), the PTC group (n = 189) and the MTC group (n = 56). The area under the curve (AUC) values were analyzed and the receiver operator characteristic (ROC) curves were drawn to compare the diagnostic efficiencies of ACR score, ACR TI-RADS and KWAK TI-RADS on benign thyroid nodules, MTC and PTC. Results: The AUC values of ACR score, ACR TI-RADS and Kwak TI-RADS for distinguishing malignant nodules from benign nodules were 0.914 (95%CI: 0.886–0.937), 0.871 (95%CI: 0.839–0.899) and 0.885 (95%CI: 0.854–0.911), respectively. In distinguishing of patients with MTC from PTC, the AUC values of ACR score, ACR TI-RADS and Kwak TI-RADS were 0.650 (95%CI: 0.565–0.734), 0.596 (95%CI: 0.527–0.664), and 0.613 (95%CI: 0.545–0.681), respectively. The AUC values of ACR score, ACR TI-RADS and Kwak TI-RADS for the discrimination of patients with MTC, PTC or benign nodules from patients without MTC, PTC or benign nodules were 0.899 (95%CI: 0.882–0.915), 0.865 (95%CI: 0.846–0.885), and 0.873 (95%CI: 0.854–0.893), respectively. Conclusion: The ACR score performed the best, followed ex aequo by the ACR and Kwak TI-RADS in discriminating patients with malignant nodules from benign nodules and patients with MTC from PTC. [ABSTRACT FROM AUTHOR]

The ciliate phylum is a group of protists noted for their unusual membrane trafficking system and apparent environmental ubiquity; as highly successful microbial predators, they are found in all manner of environments and the ability for specific species to adapt to extremely challenging conditions makes them valued as bioindicators. Ciliates have also been used for many years as cell biological models because of their large cell size and ease of culturing, and for many fundamental cell structures, particularly membrane‐bound organelles, ciliates were some of the earliest organisms in which these were observed via microscopy. In this study, we carried out a comparative genomic survey of selected membrane trafficking proteins in a pan‐ciliate transcriptome and genome dataset. We observed considerable loss of membrane trafficking system (MTS) proteins that would indicate a loss of machinery that is generally conserved across eukaryotic diversity, even after controlling for potentially incomplete genome representation. In particular, the complete DSL1 complex was missing in all surveyed ciliates. This protein complex has been shown as involved in peroxisome biogenesis in some model systems, and a paucity of DSL1 components has been indicative of degenerate peroxisome. However, Tetrahymena thermophila (formerly Tetrahymena pyroformis) was one of the original models for visualizing peroxisomes. Conversely, the AP3 complex essential for mucocyst maturation in T. thermophila, is poorly conserved despite the presence of secretory lysosome‐related organelles across ciliate diversity. We discuss potential resolutions for these apparent paradoxes in the context of the heterogenous distribution of MTS machinery across the diversity of ciliates. [ABSTRACT FROM AUTHOR]

Abstract The relevant role of long non-coding RNAs (lncRNAs) in cancer is currently a matter of increasing interest. Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor (2–5% of all thyroid cancer) derived from the parafollicular C-cells which secrete calcitonin. About 75% of all medullary thyroid cancers are believed to be sporadic medullary thyroid cancer (sMTC), whereas the remaining 25% correspond to inherited cancer syndromes known as Multiple Endocrine Neoplasia type 2 (MEN2). MEN2 syndrome, with autosomal dominant inheritance is caused by germline gain of function mutations in RET proto-oncogene. To date no lncRNA has been associated to MEN2 syndrome and only two articles have been published relating long non-coding RNA (lncRNA) to MTC: the first one linked MALAT1 with sMTC and, in the other, our group determined some new lncRNAs in a small group of sMTC cases in fresh tissue (RMST, FTX, IPW, PRNCR1, ADAMTS9-AS2 and RMRP). The aim of the current study is to validate such novel lncRNAs previously described by our group by using a larger cohort of patients, in order to discern their potential role in the disease. Here we have tested three up-regulated (RMST, FTX, IPW) and one down-regulated (RMRP) lncRNAs in our samples (formalin fixed paraffin embedded tissues from twenty-one MEN2 and ten sMTC patients) by RT-qPCR analysis. The preliminary results reinforce the potential role of RMST, FTX, IPW and RMRP in the pathogenesis of MTC.

Machine Type Communication (MTC) becomes one of enablers of the internet of things, it faces many challenges in its integration with human-to-human (H2H) communication methods. To this aim, the Long Term Evolution (LTE) needs some adaptation in the scheduling algorithms that assign resources efficiently to both MTC devices (MTCDs) and H2H users. The minimum amount of LTE resources that can be assigned to one user is much larger than the requirements of a single MTCD. In this paper, a QoS-enabled algorithm is proposed to aggregate MTCD traffic coming from many sources at the Relay Node (RN) that classifies and aggregates the MTCD traffic based on the source type and delay requirements. In this study, three types of MTCD and one H2H sources will be considered. Each type of MTCD traffic will be grouped into a separate queue, and will be served with the appropriate priority. Resources are then assigned to the aggregated MTC traffic instead of an individual assignment for each MTCD, while the H2H users will be directly connected to the LTE. Two schemes of resource partitioning and sharing between the MTCDs and the H2H users will be considered: one proportional and the other moving-boundary. Simulation models will be built to evaluate the proposed algorithms. While the obtained results for the first scheme showed a clear improvement in LTE resource utilization for the MTCDs, a negative effect was noticed in the performance of the H2H users. The second scheme achieved a positive improvement for both MTCDs and H2H users.

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and life-threatening hypersensitivity reaction. It is characterized by fever, skin lesions, and internal organ involvement. Sorafenib is a tyrosine kinase inhibitor that is used for the treatment of certain cancers such as hepatocellular, renal cell, and thyroid cancer. Case Presentation: The case is a 40 years old man who presented with fever, generalized skin rash, and pruritus. The patient has received sorafenib for the treatment of medullary thyroid cancer (MTC) from 3 weeks ago. Following presentation, the drug was discontinued and causality was assessed by scoring system RegiSCAR and Naranjo scale that showed a probable DRESS. There was no internal organ involvement based on the laboratory evaluations. The considerable abnormality was eosinophilia among patient's laboratory tests. Antihistamines and topical and systemic corticosteroids were utilized for the management of the symptoms. Conclusion: To the best of our knowledge, this is the first case report of DRESS syndrome by sorafenib in the patients with MTC. Clinicians should be aware of sign and symptoms suggesting DRESS syndrome of sorafenib. [ABSTRACT FROM AUTHOR]

For the different random access requirements of the mixed scenarios of ultra-reliable low latency (URLLC) and massive machine type communications (mMTC) in MTC,a random access scheme based on devices grouping was proposed.The proposed scheme divided the MTC devices into several groups based on the timing advance (TA) information:for the URLLC scenario,preamble resources were reserved for core devices in each group,and the URLLC devices accessed the network via the contention-free mechanism,to satisfy the ultra-reliable low latency access requirement; for the mMTC scenario,the base station utilized the different TA information in different group to identify devices selecting the same preamble,and performed successive interference cancellation (SIC) algorithm to detect the data information,to satisfy the massive access requirement.Simulation results demonstrate that the proposed scheme can significantly increase the number of the successful devices.

Effective resource allocation has always been one of the serious challenges in wireless communication. A considerable number of machine type communication (MTC) devices in 5G with variable quality of service (QoS) aggravates this challenge even further. Existing Resource allocation schemes in MTC are usually considering signal to noise ratio (SNR), which provides preference to MTC devices based on distance rather than their QoS requirements. This paper proposes a resource allocation scheme with dynamic priorities for MTC devices with multiple radio access technologies (RATs). The proposed resource allocation scheme has two main parts namely medium access and resource allocation. The medium access leverages the broadcast nature of wireless signal and MTC devices' wait time to assign priorities using capillary band in a secure and integral way. At resource allocation, SNR, total induced transmission delay, and transmission-awaiting MTC devices are used to assign resources in the cellular band. The rumination of two-staged dynamic priorities in the proposed scheduling scheme brings significant performance improvements in outage and success probabilities. Compared to SNR-based schemes, the proposed mechanism performs well by expressively improving the outage and success probability by 20% and 30%, respectively.

Blood iron levels play a vital role in oxygen metabolism and energy generation whilst transporter protein, transferrin, binds and delivers iron to the transferrin receptor of endosomal compartments of cells. Consequently, the iron-binding capacity of transferrin is an important indicator for many diseases, and its measurements are used in the diagnosis and treatment of anaemias. Various assays, including Total Iron Binding Capacity (TIBC), Unsaturated Iron-Binding Capacity (UIBC) and Transferrin Saturation (TS), were developed to assess the iron-binding capacity of transferrin. Clinically, UIBC is measured in serum by a multi-step liquid ferrozine method and subjected to interference from conditions such as haemolysis and lipemia. Here, we report a quick method that directly measures the concentration of apotransferrin in EDTA-treated plasma, theoretically equivalent to UIBC. Importantly, this supramolecular assembly-based method is more time-efficient, cost-effective and insensitive to serum cation fluctuations. With additional colorimetric property, this method also provides a visual indicator for abnormal health conditions with extreme transferrin statuses such as those found in cancers. Its minimal requirement for equipment would be particularly useful for diagnosis in remote and under-developed regions.

Background: A thymoma with chest pain and multilocular thymic cysts (MTCs) is very rare. Case presentation: A 49-year-old man presented to another hospital complaining of an anterior chest pain. Chest computed tomography (CT) showed an anterior mediastinal tumor 60 × 30 × 55 mm in size. The boundary with the pericardium or left brachiocephalic vein seemed to be partially unclear while enhanced by the contrast medium, and so the tumor could have invaded them. No definitive diagnosis of myasthenia gravis was made although the serum anti-acetylcholine receptor antibody count was high. We performed an extended thymectomy with combined partial resection of left brachiocephalic vein, left upper lobe, and left phrenic nerve. He was discharged with no chest pain and no complications post-surgery. The tumor was pathologically type B2 thymoma with hemorrhage necrosis and MTCs, and we diagnosed Masaoka stage II because of no histological infiltration to the organs. Conclusions : We speculated that hemorrhagic necrosis due to infarction in tumor caused the inflammation to spread to the surrounding organs, which was related to the chest pain and the development of MTCs. [ABSTRACT FROM AUTHOR]

Current communication networks are mainly designed for Human-to-Human (H2H) communication requirements. However, future Internet of Things (IOT) and fifth-generation mobile communications system (5G) will connect a lot of mechanical equipment. Therefore, this paper proposes a priority-based predictive resource scheduling algorithm that integrates the predictive method and priority scheduling for the uplink of Massive Machine Type Communication (mMTC). The predictive method is used to reduce the delay of a device sent scheduling request to the eNodeB to obtain the approved resources for data transmission. This is combined with a priority ranking sequence to develop the optimal resource allocation strategy to reduce the total delay time, and improve the transmission success rate and resource utilization. Simulation results show that the proposed algorithm can effectively reduce delay and increase the transmission success rate, compared with the existing methods. [ABSTRACT FROM AUTHOR]

Coexistence of Human-Type Communications (HTCs) and Machine-Type Communications (MTCs) is inevitable. Ultra-Dense Networks (UDNs) will be efficacious in supporting both types of communications. In a UDN, a massive number of low-power and low-cost Small Cells (SCs) are deployed with density higher than that of the HTC users. In such a scenario, the backhaul capacities constitute an intrinsic bottleneck for the system. Hence, we propose a multiple association scheme where each HTC user associates to and activates multiple SCs to overcome the backhaul capacity constraints mainly encountered in the downlink. In addition, having more active cells allows for more MTC devices to be supported by the network. Using tools from stochastic geometry, we formulate a novel mathematical framework investigating the performance of HTC in both downlink and uplink as well as the uplink MTC. Stretched Exponential Path Loss (SEPL) model is considered to practically reflect the UDN environment. Extensive simulations were conducted to verify the accuracy of the mathematical analysis under different system parameters. Results show the existence of an optimum number of SCs to which an HTC user may connect under backhaul capacity constraints. Besides, the proposed multiple-association scheme improves the performance of MTC in terms of both ASE and density of supported devices. [ABSTRACT FROM AUTHOR]

Abstract Background Medullary thyroid carcinoma (MTC) is a rare subtype of thyroid cancer. Other than gain‐of‐function RET mutations, no other genetic, lifestyle or environmental risk associations have been established for MTC. Several case‐control studies and meta‐analysis have examined the risk association of different SNPs with MTC in different populations but with contradictory or inconclusive results. Methods In a large cohort of 438 Indian MTC cases and 489 gender and ethnicity matched healthy controls from 1000 genome project, a comprehensive risk association of 13 SNPs of three pathways—detoxification, cell cycle regulation and RET was performed along with meta‐analysis of RET SNPs. Results Multivariate logistic regression analysis identified a protective risk association of CDKN1ASer31Arg SNP with both hereditary (OR 0.26; 95% confidence interval [CI] 0.13‐0.55; P

Poupak Fallahi,1 Silvia Martina Ferrari,2 Giusy Elia,2 Francesca Ragusa,2 Sabrina Rosaria Paparo,2 Ilaria Ruffilli,2 Armando Patrizio,2 Gabriele Materazzi,3 Alessandro Antonelli21Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 2Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 3Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, ItalyCorrespondence: Alessandro AntonelliDepartment of Clinical and Experimental Medicine, School of Medicine, University of Pisa, Via Savi, 10, Pisa I-56126, ItalyTel +39 05 099 2318Fax +39 05 099 3472Email alessandro.antonelli@med.unipi.itAbstract: Medullary thyroid cancers (MTCs) are neuroendocrine tumors, which secrete calcitonin and carcinoembryonic antigen, both of which can serve as tumor markers. Extensive and accurate surgical resection is the primary treatment for MTC, whereas the use of external beam radiotherapy is limited. Moreover, since MTC is derived from thyroid parafollicular cells or C cells, it is not responsive to either radioiodine or thyroid-stimulating hormone suppression, and therefore, they cannot be considered as treatment strategies. Traditional therapies for advanced or metastatic progressive medullary thyroid cancer (pMTC) are poorly effective. Among the new approaches tested in clinical trials, targeted chemotherapies with tyrosine kinase inhibitors (TKIs) are now available and they represent effective interventions for progressive disease, with additional investigational options emerging. This paper reviews the efficacy and safety of vandetanib in patients with a pMTC, as it has been shown to improve progression-free survival (30.5 vs 19.3 months in controls). Vandetanib is approved by the FDA and EMA for symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease in adults, adolescents, and children older than 5 years. The most common adverse events in vandetanib-treated patients are diarrhea, rash, folliculitis, nausea, QTc prolongation, hypertension, and fatigue. More data are required to deepen our knowledge on molecular biology of tumor and host defense, with the aim to achieve better prognosis and higher quality of life for affected patients.Keywords: MTC, pediatric MTC, vandetanib, RET, VEGFR, AEs

Abstract Background Different pathogenic germline mutations in the RET oncogene are identified in MEN 2, a hereditary syndrome characterized by medullary thyroid carcinoma (MTC) and other endocrine tumors. Although genetic predisposition is recognized, not all RET mutation carriers will develop the disease during their lifetime or, likewise, RET mutation carriers belonging to the same family may present clinical heterogeneity. It has been suggested that a single germline mutation might not be sufficient for development of MEN 2-associated tumors and a somatic bi-allelic alteration might be required. Here we investigated the presence of somatic second hit mutation in the RET gene in MTC. Methods We integrated Multiplex Ligation-dependent Probe Amplification (MLPA) and whole exome sequencing (WES) to search for copy number alteration (CNA) in the RET gene in MTC samples and medullary thyroid cell lines (TT and MZ-CR-1). We next found reads spanning exon-exon boundaries on RET, an indicative of retrocopy. We subsequently searched for RET retrocopies in the human reference genome (GRCh37) and in the 1000 Genomes Project data, by looking for reads reporting joined exons in the RET locus or distinct genomic regions. To determine RET retrocopy specificity and recurrence, DNA isolated from sporadic and MEN 2-associated MTC (n = 37), peripheral blood (n = 3) and papillary thyroid carcinomas with RET fusion (n = 10) samples were tested using PCR-sequencing methodology. Results Through MLPA we have found evidence of CNA in the RET gene in MTC samples and MTC cell lines. WES analysis reinforced the presence of the CNA and hinted for a retroposed copy of RET not found in the human reference genome and 1.000 Genomes Project. Extended analysis confirmed the presence of a somatic MTC-related retrocopy of RET in both sporadic and hereditary tumors. We further unveiled a recurrent (28%) novel point mutation (p.G548 V) found exclusively in the retrocopy of RET. The mutation was also found in cDNA of mutated samples, suggesting it might be functional. Conclusion We here report a somatic specific RET retroposed copy in MTC samples and cell lines. Our results support the idea that generation of retrocopies in somatic cells is likely to contribute to MTC genesis and progression.

The machine-type communication (MTC) plays an essential role in the mobile network society and it has demonstrated its effectiveness to generate significant revenues for mobile network operators. The MTC has become the main communication paradigm for several emerging smart services, such as public safety, health care, industrial automation, drones/robotics, utilities, and transportation. The MTC requires a major model change to cope with the improvement in 5G and imposes various requirements on the enabling technology, such as ultra-reliability, low latency, and availability. The scheme that fulfills such requirements are called a mission-critical MTC (mcMTC). However, the mcMTC is still in the early-standardization phase of 5G new radio and it needs a lot of research efforts to be improved. This paper presents an extensive review and evaluations to highlight diverse challenges and future aspects of mcMTC on 5G-enabling technologies. A number of research opportunities from both academic communities and industrial partners are given as examples for encouragement purposes.

Jes Sloth Mathiesen,1,2 Jens Peter Kroustrup,3 Peter Vestergaard,3,4 Kirstine Stochholm,5,6 Per Løgstrup Poulsen,6 Åse Krogh Rasmussen,7 Ulla Feldt-Rasmussen,7 Sten Schytte,8 Stefano Christian Londero,8 Henrik Baymler Pedersen,9 Christoffer Holst Hahn,10 Jens Bentzen,11 Sören Möller,2,12 Mette Gaustadnes,13 Maria Rossing,14 Finn Cilius Nielsen,14 Kim Brixen,2 Anja Lisbeth Frederiksen,2,15 Christian Godballe1 On behalf of the Danish Thyroid Cancer Group (DATHYRCA) 1Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark; 2Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 4Steno Diabetes Center North Jutland, Aalborg, Denmark; 5Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark; 6Center for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark; 7Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark; 8Department of ORL Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark; 9Department of ORL Head & Neck Surgery, Aalborg University Hospital, Aalborg, Denmark; 10Department of ORL Head & Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark; 11Department of Oncology, Herlev Hospital, Herlev, Denmark; 12Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark; 13Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 14Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark; 15Department of Clinical Genetics, Odense University Hospital, Odense, Denmark Background: The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested.Methods: The study included 200 patients identified from the nationwide Danish MTC cohort 1997–2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994–2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested.Results: Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81–0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76–0.88; 131/158). Completeness was 88% (95% CI: 0.75–0.95; 42/48) and 81% (95% CI: 0.72–0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested.Conclusion: The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test. Keywords: RET testing, medullary thyroid carcinoma, Denmark

There is a growing interest in the transition from 4-step random access to 2-step random access in machine-type communication (MTC), since 2-step random access is well-suited to short message delivery in various Internet of Things (IoT) applications. In this paper, we study a 2-step random access approach that uses code division multiple access (CDMA) to form multiple channels for data packet transmissions with a spreading factor less than the number of channels. As a result, the length of data transmission phase in 2-step random access can be shorter at the cost of multiuser interference. To see how the decrease of the length of data transmission phase can improve the spectral efficiency, we derive the throughput as well as the spectral efficiency. From the results of analysis, we can show that the 2-step CDMA-based random access approach can have a higher spectral efficiency than conventional 2-step approach with orthogonal channel allocations, which means that the performance of MTC can be improved by successfully transmitting more data packets per unit time using CDMA. This is also confirmed by simulation results. [ABSTRACT FROM AUTHOR]

The relevant role of long non-coding RNAs (lncRNAs) in cancer is currently a matter of increasing interest. Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor (2-5% of all thyroid cancer) derived from the parafollicular C-cells which secrete calcitonin. About 75% of all medullary thyroid cancers are believed to be sporadic medullary thyroid cancer (sMTC), whereas the remaining 25% correspond to inherited cancer syndromes known as Multiple Endocrine Neoplasia type 2 (MEN2). MEN2 syndrome, with autosomal dominant inheritance is caused by germline gain of function mutations in RET proto-oncogene. To date no lncRNA has been associated to MEN2 syndrome and only two articles have been published relating long non-coding RNA (lncRNA) to MTC: the first one linked MALAT1 with sMTC and, in the other, our group determined some new lncRNAs in a small group of sMTC cases in fresh tissue (RMST, FTX, IPW, PRNCR1, ADAMTS9-AS2 and RMRP). The aim of the current study is to validate such novel lncRNAs previously described by our group by using a larger cohort of patients, in order to discern their potential role in the disease. Here we have tested three up-regulated (RMST, FTX, IPW) and one down-regulated (RMRP) lncRNAs in our samples (formalin fixed paraffin embedded tissues from twenty-one MEN2 and ten sMTC patients) by RT-qPCR analysis. The preliminary results reinforce the potential role of RMST, FTX, IPW and RMRP in the pathogenesis of MTC. [ABSTRACT FROM AUTHOR]

Semisolid magnetization transfer contrast (MTC) and chemical exchange saturation transfer (CEST) MRI based on MT phenomenon have shown potential to evaluate brain development, neurological, psychiatric, and neurodegenerative diseases. However, a qualitative MT ratio (MTR) metric commonly used in conventional MTC imaging is limited in the assessment of quantitative semisolid macromolecular proton exchange rates and concentrations. In addition, CEST signals measured by MTR asymmetry analysis are unavoidably contaminated by upfield nuclear Overhauser enhancement (NOE) signals of mobile and semisolid macromolecules. To address these issues, we developed an MTC-MR fingerprinting (MTC-MRF) technique to quantify tissue parameters, which further allows an estimation of accurate MTC signals at a certain CEST frequency offset. A pseudorandomized RF saturation scheme was used to generate unique MTC signal evolutions for different tissues and a supervised deep neural network was designed to extract tissue properties from measured MTC-MRF signals. Through detailed Bloch equation-based digital phantom and in vivo studies, we demonstrated that the MTC-MRF can quantify MTC characteristics with high accuracy and computational efficiency, compared to a conventional Bloch equation fitting approach, and provide baseline reference signals for CEST and NOE imaging. For validation, MTC-MRF images were synthesized using the tissue parameters estimated from the deep-learning method and compared with experimentally acquired MTC-MRF images as the reference standard. The proposed MTC-MRF framework can provide quantitative 3D MTC, CEST, and NOE imaging of the human brain within a clinically acceptable scan time.

In this paper, we report the design, synthesis and biological evaluation of a novel S-allyl-l-cysteine (SAC) and gallic acid conjugate S-(4-fluorobenzyl)-N-(3,4,5-trimethoxybenzoyl)-l-cysteinate (MTC). We evaluate the effects on ischemia-reperfusion-induced PC12 cells, primary neurons in neonatal rats, and cerebral ischemic neuronal damage in rats, and the results showed that MTC increased SOD, CAT, GPx activity and decreased LDH release. PI3K and p-AKT protein levels were significantly increased by activating PI3K/AKT pathway. Mitochondrial pro-apoptotic proteins Bax and Bim levels were reduced while anti-apoptotic protein Bcl-2 levels were increased. The levels of cleaved caspase-9 and cleaved caspase-3 were also reduced in the plasma. The endoplasmic reticulum stress (ERS) was decreased, which in turns the survival rate of nerve cells was increased, so that the ischemic injury of neurons was protected accordingly. MTC activated the MEK-ERK signaling pathway and promoted axonal regeneration in primary neurons of the neonatal rat. The pretreatment of MEK-ERK pathway inhibitor PD98059 and PI3K/AKT pathway inhibitor LY294002 partially attenuated the protective effect of MTC. Using a MCAO rat model indicated that MTC could reduce cerebral ischemia-reperfusion injury and decrease the expression of proinflammatory factors. The neuroprotective effect of MTC may be due to inhibition of the over-activation of the TREK-1 channel and reduction of the current density of the TREK1 channel. These results suggested that MTC has a protective effect on neuronal injury induced by ischemia reperfusion, so it may have the potential to become a new type of neuro-ischemic drug candidate.

Wireless networks beyond 5G will mostly be serving myriads of sensors and other machine-type communications (MTC), with each device having different requirements in respect to latency, error rate, energy consumption, spectral efficiency or other specifications. Multiple-input multiple-output (MIMO) systems remain a central technology towards 6G, and in cases where massive antenna arrays or cell-free networks are not possible to deploy and only moderately large antenna arrays are allowed, the detection problem at the base-station cannot rely on zero-forcing or matched filters and more complex detection schemes have to be used. The main challenge is to find low complexity, hardware feasible methods that are able to attain near optimal performance. Randomized algorithms based on Gibbs sampling (GS) were proven to perform very close to the optimal detection, even for moderately large antenna arrays, while yielding an acceptable number of operations. However, their performance is highly dependent on the chosen “temperature” parameter (TP). In this paper, we propose and study an optimized variant of the GS method, denoted by triple mixed GS, and where three distinct values for the TP are considered. The method exhibits faster convergence rates than the existing ones in the literature, hence requiring fewer iterations to achieve a target bit error rate. The proposed detector is suitable for symmetric large MIMO systems, however the proposed fixed complexity detector is highly suitable to spectrally efficient adaptively modulated MIMO (AM-MIMO) systems where different types of devices upload information at different bit rates or have different requirements regarding spectral efficiency. The proposed receiver is shown to attain quasi-optimal performance in both scenarios.

Long-Term Evolution-Advanced (LTE-A) networks have been regarded as having great potential to support the Internet of Things (IoT). However, the high probability of preamble collisions when massive numbers of IoT devices try to access the network within a short period has become a significant problem. In this paper, we propose a new scheme to efficiently handle the initial access contention for massive numbers of IoT devices in LTE-A networks. The proposed scheme divides an entire preamble set into $k$ subgroups; then, contention resolution is performed in each subgroup independently in a parallel and pipelined manner. Simulation results show that our scheme leads to considerable improvement in terms of average access delay and standard deviation of access delays without increasing blocking probability. Moreover, utilization of preamble resources is greatly improved by reducing the number of random access slots, where only a few devices participate in preamble selection.

This paper focuses on edge-enabled cloud radio access network architecture to achieve ultra-reliable communication, a crucial enabler for supporting mission-critical machine-type communication networks. We propose coordinated multi-point transmission schemes taking advantage of diversity mechanisms in interference-limited downlink cellular networks. The network scenario comprises spatially distributed multiple remote radio heads (RRHs) that may cooperate through silencing, or by using more elaborated diversity strategies such as maximum ratio transmission or transmit antenna selection to serve user equipment in the ultra-reliable operation regime. We derive an exact closed-form expression for the outage probabilities and expected values of signal-to-interference ratio for silencing, transmit antenna selection and maximum ratio transmission schemes. We formulate rate control and energy efficiency under reliability constraints to test the performance and resource usage of the proposed schemes. Furthermore, we study the impact on average system sum throughput with throughput-reliability trade-off under cooperative communication. Extensive numerical analysis shows the feasibility of ultra-reliable communication by implementing diversity schemes with RRHs cooperation.