Uterine fibromas are the most common benign uterine tumors. Although the majority of leiomyomas remain asymptomatic, they can cause serious clinical problems, including abnormal uterine bleeding, pelvic pain, and infertility, which require effective gynecological intervention. Depending on the symptoms as well as patients’ preferences, various treatment options are available, such as medical therapy, non-invasive procedures, and surgical methods. Regardless of the extent of the surgery, the preferred option is the laparoscopic approach. To reduce the risk of spreading occult malignancy and myometrial cells associated with fragmentation of the specimen before its removal from the peritoneal cavity, special systems for laparoscopic contained morcellation have been developed. The aim of this review is to present the state-of-the-art contained morcellation. Different types of available retrieval bags are demonstrated. The advantages and difficulties associated with contained morcellation are described. The impact of retrieval bag usage on the course of surgery, as well as the effects of the learning curve, are discussed. The role of contained morcellation in the overall strategy to optimize patient safety is highlighted. Uterine leiomyomas [fibroids] are the most commonly diagnosed form of benign gynecological tumors, consisting of smooth muscle and abnormal dysfunctional extracellular matrix. Although uterine myomas occur in up to 80% of women of reproductive age ,2,3,4, tFor women who wish to avoid surgery, contemporary gynecology offers numerous treatment options, including hormonal therapy and antifibrinolytic or non-steroidal anti-inflammatory drugs ,9,10. FoFor symptomatic women, after ineffective medical and/or non-invasive treatment, surgical procedures are offered . SurgicaKeeping in mind the prevalent symptoms and the preferences of the patient, the final decision on the selection of treatment modality is guided by imaging techniques, mainly ultrasound examination and magnetic resonance imaging . UltrasoDespite the relatively wide availability of the numerous, above-listed conservative management options, surgical procedures still remain the basic treatment form for uterine fibroids. The spectacular development of laparoscopic technology has led to the vast majority of leiomyoma open operations being carried out via laparoscopy. This change in surgical approach is supported by the well-known advantages of laparoscopy, such as minimal traumatizing of the abdominal wall, excellent cosmetic effect, and a quick return to health and full physical activity. Except for cases of total laparoscopic hysterectomy followed by transvaginal removal of the uterus, all the remaining laparoscopic operations related to leiomyomas include sharp fragmentation of the specimen. This technique, called power morcellation, was introduced by Steiner and first described in 1993 . Since tConsidering these facts, and the FDA’s warning, operating gynecologists faced a real decisional dilemma because the undeniable advantages of minimal-access surgery could not be overlooked . AdditioThe aim of this brief review is to offer a comprehensive update on contained laparo-scopic morcellation and to indicate future challenges. We focus on practical aspects of bag use and its impact on the course of the operation.A comprehensive search was conducted on PubMed (2014–2023) and Scopus (2014–2023). Several keywords and their combinations were used to retrieve articles from these databases, including contained morcellation, in-bag morcellation, power morcellation, endobag, myomectomy, hysterectomy, leiomyosarcoma, and malignancy dissemination. Articles were included if they were cohort, clinical, case–control studies, or case series. Case reports and studies involving animals were excluded.Laparoscopic morcellation with the use of a retrieval bag was first reported by urologists in 1993 . SubsequThe history of in-bag morcellation in gynecological surgery is also quite rich. To date, various techniques have been reported, which differ from each other in terms of indication, installation of the bag, type of morcellation, and ways of removing tissue. As far as approach is concerned, bags were introduced through the abdominal port site, transvaginally, or via laparotomic incision ,76,77,78Currently, the most frequently used are the second-generation containers, called two-port or dual opening bags. They are usually made of polyurethane or polyurethane-coated nylon fabric ,64,65. TThe typical dual opening bag has two separate ports .The diameter of the main opening varies between 13 and 17 cm, depending on the size of the bag and the manufacturer. This opening is used to put a specimen into the bag, which might be myoma/myomas, corpus uteri, the entire uterus, etc., according to conducted procedure. The large opening also serves as morcellator access. The second port (opening) is designed for the insertion of the optic trocar at the umbilical site. It is sleeve-shaped, narrow (about 15–17 mm), and long (10–19 cm). In some of the systems, the second opening (second sleeve) is double-layered ,63. AfteOnce the specimen is positioned, the large opening is closed by pulling the drawstring and extracted outside the abdominal wall .2. Next, the morcellator is entered bluntly into the bag through its large opening. The power morcellation proceeds in a contained space, but its technique remains unchanged. Once the morcellation is completed, the electro-morcellator, as well as the optic, are removed from the bag. Small pieces of specimen and a certain volume of blood remain in the bag. Depending on the study, the median weight of the bag content varies from 12 to 29 g [The second opening is pulled out through the umbilical access while the previously inserted optic trocar is removed. At this point, the recently removed optic trocar is reinserted into the bag via the small tubular opening and so-called pseudoperitoneum is established by inflating with CO to 29 g ,83. This to 29 g ,63.Recent years have brought a new solution in the field of closed morcellation, the so-called third-generation bag, which is a multiport retrieval container. Apart from a large opening, it is equipped with three working ports, through which instruments of a diameter up to 15 mm can be inserted, for example graspers or irrigator. The large mouth is self-opening. Sealable access points allow safe retrieval of the bag. Multiport bags are not yet widely spread, and publications relating to their use are lacking.Introducing the new bag systems to the routine surgical practice was preceded by thorough preclinical evaluation of its ability to diminish the risk of fluid and cell dissemination during the surgical procedures. The properties of the bag material were first tested in vitro, where the morcellation of animal tissue in a laparoscopy training set was performed with the usage of typical laparoscopic instrumentarium . As a neInsertion of the retrieval bag into the peritoneal cavity;Deployment of the bag;Positioning of the bag inside the abdominal cavity;Positioning the specimen into the bag;Large-opening exterioration;Exterioration of the optic sleeve;Insertion of the umbilical trocar;Establishing the pseudoperitoneum;Introduction of the telescope into the inflated bag;Initial and continuous in-bag visualization;Insertion of the morcellation device;Manipulation of the specimen within the bag to find the optimal position for morcellation;Course of the in-bag morcellation;Morcellation-associated complications;Uncontaminated closing of the optic sleeve;Removal of the bag;Damage of the containment bag;Occurrence of any organ damage related to bag use;Other intraoperative complications;Time necessary to conduct particular steps of the procedure;Overall satisfaction of the operating doctor.To objectively assess the practical utility of a retrieval bag and the impact of contained morcellation on the entire course of the operation, numerous aspects of the procedure and its specific phases must be taken into consideration. They involve in particular:Generally, numerous publications have confirmed in-bag morcellation to be feasible and satisfactory ,66,82,84In-bag morcellation, as any other new operating technique, has its own learning curve. Observations demonstrate that systematic training allows for a reduction in the median total time related to bag use from 14 to 10 min. Another positive aspect of the learning curve is the growth in the technical success rate, which is reported to increase from 85.7% to 93.9% ,82. WhilAs shown above, the laparoscopic contained morcellation technique requires additional time for bag use. However, this approach also saves time, because the meticulous collection of tissue remnants and extensive washing of the abdominal cavity, typical for uncontained morcellation, is not necessary. The study of Krentel et al. demonstrated that this effect can be spectacular. According to these authors, after one year of use of the retrieval bag, the duration of the entire procedure with in-bag morcellation, from first skin incision to the last suture, does not differ from its counterpart with uncontained morcellation. What is more, after 2 years of regular practice, the total surgical time with use of the bag is significantly shorter than in a control group .Another advantage of using the retrieval bag is the walls of the inflated bag pushing up intestinal slings. This makes the operating space more comfortable for the surgeon and simultaneously safer for the patient.Despite the relatively high success rate, difficulties with handling of the bag happen in about 16% of cases. A too small umbilical fascia incision may cause problems with optic trocar placement into the optic sleeve, which leads to repeated attempts of insertion or additional enlarging of the fascia opening. Sometimes the bag remains twisted after insertion and requires removal with subsequent replacement .According to published studies, the weight of the surgical specimen subjected to contained morcellation varied from 18 to 2805 g ,65,82,87The risk of bag damage with subsequent tissue dissemination depends on the type of tissue extraction system, applied surgical technique, experience of the operating team, and the size of the specimen. Early studies reported damage to the bag in about 6% of cases . This haAdverse events associated with bag use seem to be very rare. Numerous studies report no complications ,65,82,87There is a paucity of research comparing different bag systems for contained morcellation. The only recently published study involved 33 women with uterine fibromas or adenomyosis, who were alternately allocated to a different retrieval bag system group . The firThe presented review has several limitations. There are no randomized control trials comparing laparoscopic uncontained and in-bag morcellation. Available studies are mainly retrospective and include limited numbers of patients. Finally, the definition of bag-related complications varies between studies, a fact which hinders proper interpretation.Minimally invasive approaches, especially the laparoscopic technique, have significantly changed contemporary gynecology and are currently considered the “gold standard” in uterine fibroids surgery. Power morcellators were developed as a response to the requirement for special techniques to remove the specimen from the abdominal cavity inherent in the use of minimally invasive access. A 2014 FDA safety communication discouraged the routine use of open morcellation, given concerns for iatrogenic dissemination of a previously undiagnosed malignancy. Despite the unresolved issue of the occurrence and significance of this phenomenon, and even existing doubts whether a myoma can develop or transform into a sarcoma, all possible measures must be taken to optimize patient safety. Contained morcellation is considered to be one such solution that reduces the potential intraabdominal spread of undetected malignancy and myometrial cells, while simultaneously maintaining the benefits of a minimally invasive surgical approach. During the last decade, an intensive development of contained morcellation systems was observed—from single-port to multiport retrieval bags. Research has revealed positive learning curve effects, resulting in a reduction in the time associated with bag use and an increase in the size of the specimen successfully subjected to in-bag morcellation. The use of containment systems did not increase the rate of perioperative complications. However, it is essential to remember that in-bag morcellation is just one of the aspects of protecting patient safety. Qualification for laparoscopic uterine fibroids surgery with contained morcellation should be preceded by meticulous preoperative diagnosis, careful consideration of the advantages and risks of the planned approach, and thorough patient counseling. Further clinical trials are needed to more precisely determine the impact of the use of containment bags on the course of the operation as well as its effectiveness in the prevention of intraperitoneal tissue dissemination.


Revisions of classical models of acute stress response spectrum and defence cascade process might represent a valuable background for the interpretation of the link between affective reactions, traumatic experiences, and Psychogenic pseudosyncope (PPS) events in childhood and across the lifespan. Indeed, associations between subjective emotional life, early exposure to distressing and/or traumatic events, and PPS have fuelled a debate on potential causes of occurrence and recurrence of such a peculiar clinical manifestation. At the same time, such background suggests that empowering stress management and affective regulation skills could be the target for neurorehabilitation interventions aiming at reducing the severity of symptomatology and/or improving awareness and management of pseudosyncopal spells. Specifically, neuro/biofeedback-based empowerment of self-regulation skills, associated to an increased interoceptive increased awareness, could be a promising complement to classical psychological therapies. Starting from the presentation of a paediatric PPS clinical case, the present work discusses the relevance of assessing affective appraisal and autonomic reactivity in individuals suffering from PPS episodes and introduces a novel potential neuroempowerment protocol aimed at improving self-regulation and stress management skills in adolescence based on a combined neurofeedback and embodied-awareness intervention. By capitalizing available evidence of the effects of neuromodulation and embodied practices on self-awareness/regulation across the life-span, the proposed protocol is based on neurofeedback-supported affective management training, as well as both contemplative and informal awareness exercises devised to be appealing and challenging even for younger patients. Exposure to trauma in the early and mid steps of the lifespan can, indeed, have a pervasive impact on psychological, physical, and neural development, with a wide and robust evidence base highlighting its implication in far-ranging psychopathology, including depression, anxiety, suicide attempts, psychosis, substance use disorders, personality disorders, and self-regulatory disorders –9. MoreoAccording to recent literature reviews, a further transdiagnostic features of atypical developmental trajectories might be the compound impairment of interoceptive sensitivity/awareness, dysregulation of physiological homeostasis and stress responses, and altered affective regulation –17. As aMore specifically, the link between the ability to effectively process internal sensations and focus on internal states and proficiency in controlling behaviour and self-regulation has been stressed, with alterations in interoceptive awareness being associated with health conditions –24, depr2.When facing affective regulation as a potential target for neurorehabilitation protocols, a first main challenge is posed by the complex interplay between conscious and unconscious processes that shapes the regulation of emotions and affects . The serEntering the domain of neurocognitive enhancement , the the(i)capturing and real-time monitoring the central physiological modifications  that accompany some mental states ;(ii)strengthening the ability to become aware of such modifications;(iii)and improving the ability to exercise intentional control over those mental states through the development of individual strategies and trough training of emotional self-regulation, attention regulation, and executive control skills.Individual strategies are specifically developed to interrupt unwanted automatic reactions  or lower their intensity or effect, and are created and strengthened during neurofeedback practice.Among psychophysiological techniques used to promote brain plasticity during neurocognitive enhancement and neurorehabilitation interventions, we propose that neurofeedback should be considered a quite promising one even when adolescents are the target of the intervention. Going down to specifics, neurofeedback is an applied psychophysiological technique which, by including the practitioner in a virtuous circle of implicit learning, primarily aims at:The neurofeedback technique pursues that threefold objective by, at first, accurately measuring one or more biosignals, understood as measurable physiological signals that mirror the fluctuation of the activity of a neural network or system. Such signals are, then, processed in real time via predetermined data processing pipelines and automated classifiers. Finally, the quantification of biosignal modulations is translated into easy-to-understand feedbacks  that are presented to the practicers via dedicated software. Those feedbacks generally consist of sounds that change in intensity and/or tone, animated graphs that change according to physiological activations, moving animations or videogames that adapts and responds to changes in bodily activity. Going down to specifics, the feedbacks provided by the software managing the neurofeedback system  are typically devised to linearly mirror the modulation of a targeted biosignal , so that any electrophysiological is recorded and used to modulate rewards and punishments that foster implicit learning. In addition, it is worth noting that thresholds for proving rewarding and/or punishing feedbacks can be both set manually and actively controlled by the trainer, or set to be automatically managed by the software, which, in such cases, would autonomously adapt them to keep a constant reward rate depending on the actual real-time practicer's performance.The intrinsic advantage of this technique consists in the degree of active involvement and agentive commitment required to the trainee in order for the technique to fully express its potential. The enhancement of cognitive-affective abilities and related neuroplastic changes that are pursued by practice are, indeed, reached by training the sensitivity of monitoring and active control of the neurofunctional substrate of those trained abilities. To reach such goal, neurofeedback requires the intentional commitment and active involvement of the practitioner, as well as a minimal degree of metacognitive and self-reflection skills. Those operational aspects of the neurofeedback technique become particularly valuable when focusing on adolescents as targets of the intervention. They might, indeed, foster self-efficacy while taking advantage of the intrinsic drive towards self-determination and expression of an actual agentive role that connote such period of life.(i)the central physiological modifications associated with a task ,(ii)the presence of an external feedback provided by the system ,(iii)an implicit associative learning process ,(iv)and the consequent consolidation of trained cognitive or affective regulation functions ,which animate and consolidate the empowerment process towards greater self-awareness and greater self-regulation skills.Neurofeedback systems thus provide practicers with real-time information on the modulation of their physiological activation states or their neurofunctional activity at rest or during the execution of a task. Audio-visual feedbacks act as the fuel for implicit learning processes and for consolidation of individual strategies developed to try and control those states and those physiological correlates of self-regulation processes. By exploiting the principles of operant conditioning, in fact, the neurofeedback systems return positive  and negative  feedback on the progress of mental training to the practicer, thus giving him/her the opportunity to directly evaluate the effect of their own efforts and gain awareness even on that self-enhancement process. The virtuous cycle created by neurofeedback systems is thus made up of four main interdependent elements, namelyRelevant to the application of the neurofeedback technique for enhancement and rehabilitation of affective regulation, it has been suggested that the specific potential of such a technique to make even minimal modifications of the neurofunctional correlates of trained mental processes easily perceptible may contribute to the learning process and maintenance of training effects , 39. AccTechnically speaking, in neurofeedback protocols, one or two sensors are typically used to collect information on the electrophysiological correlates of cognitive activity and return this information to the practitioner. The recording system amplifies and transfers the biosignals detected by the sensors to a software, which finally converts collected pieces of information into simple positive or negative feedback or, as is the case in the most recent devices, uses them to control videogames designed to train specific functions—such as focused or sustained attention skills, adaptive relaxation, or up/downregulation of emotion processing systems . All episodes occurred in the presence of witnesses, in social contexts and mostly at school. In none of them, the suspected syncopal event led to contusion or physical trauma from the fall. No evidence for actual loss of movement control or consciousness, nor for post-ictal confusion or drowsiness, was provided. ECG monitoring during the events highlighted normal cardiac responses and mild tachycardia. Following specialist clinical and instrumental examinations, A's clinical picture has been attributed to a form of suspected psychogenic pseudosyncope (PPS).Both clinical observations and cohort studies highlighted that PPS and medically unexplained syncopal events are often associated to distressing situations and emotional triggers –46. ConsAn alteration of psychophysiological responsiveness to emotional stimuli was observed even in A during standardized psychophysiological assessment . Namely,Based on that emerging psychophysiological profile, empowering aware affective regulation skills and enhancing neurofunctional structures supporting regulation of emotion and psychophysiological reactions could be deemed a primary intervention target. Available literature on neurofeedback interventions on affective regulation mainly grounds on the dual prefrontal system model of emotion processing –56, whic4.Since initial applications of the neurofeedback technique in experimental and clinical context –60, its More recently, however, research has begun to show interesting results with respect to the enhancement of stress management and affective regulation when using an integrated approach that combines neurofeedback technique with mental training based on mindfulness approach and body awareness , 63–67. a priori expectations. Such neurocognitive enhancement protocols, given their sustainable nature and due to their easy integration with other complementing neurorehabilitation interventions, might be a promising supportive therapy.Therefore, it is necessary to consider the role that the neurofeedback technique assumes in the patient's ability to develop a greater awareness of his own affective and interoceptive correlates, as a discriminating element for the ability to understand his/her own emotional states and modulate them, especially in conditions of emotional dysregulation. Building on available evidence, we suggest that the efficacy of combined mindfulness-neurofeedback protocols in atypically developing children and adolescents presenting affective regulation impairments  could be worth of systematic empirical testing, so to properly assess their potential with such populations and for such therapeutic challenges over To sum up, yet immature affective regulation strategies in adolescence, together with still evolving higher-order cognitive, self-awareness, and emotion appraisal skills, makes the impact of distressing and/or traumatic events in this period a substantial risk factor for psychopathology and atypical development, with both neurocognitive and psychiatric sequelae that should become targets for personalized rehabilitation interventions.


Photon-counting computed tomography (PCCT) is an emerging technology that is expected to radically change clinical CT imaging. PCCT offers several advantages over conventional CT, which can be combined to improve and expand the diagnostic possibilities of CT angiography. After a brief description of the PCCT technology and its main advantages we will discuss the new opportunities brought about by PCCT in the field of vascular imaging, while addressing promising future clinical scenarios. Computed tomography angiography (CTA) is actually considered the “gold” standard for the non-invasive assessment and diagnosis of vascular abnormalities ,2. CTA eCurrent cutting-edge clinical CT systems are equipped with energy-integrating detectors (EIDs), which can provide images with quantitative information such as tissue-specific images and maps of the iodine concentration. With this technology, the spatial and contrast resolutions have been improving with quite small steps over the years. A different detection concept, which has gained increasing interest and is expected to substantially modify clinical CT imaging, is photon-counting detectors (PCDs). PCDs have multiple potential advantages over conventional EIDs, which can be combined to improve and expand the diagnostic possibilities of the CTA ,5,6.After a brief description of the photon-counting CT (PCCT) technology and its main advantages, this review will focus on its clinical applicability in the realm of vascular imaging, without considering the coronary and carotid districts. We will describe both the existing literature, which is still limited, and our current experience, with the aim of providing an idea of the potential clinical implementation and diagnostic impact. Therefore, several PCCT images acquired in our department will be provided as a proof of concept.EIDs are composed of scintillator elements and septa. The scintillator converts the incident X-rays into visible light photons, that are then absorbed by a photodiode which produces an electrical signal proportional to the energy deposited and comprising also electronic noise . The sepInstead, PCDs consist of a single thick layer of a semiconductor diode on which a large voltage is applied; incoming X-ray photons are directly converted into electronic signals ,6,7. TheSince PCDs do not require septa, there is no technical limitation for the pixel pitch and its size can be significantly reduced without negatively impacting the geometric detection efficiency. This translates into an increased spatial resolution, that can be exploited to generate sharper images and visualize finer details ,8.In conventional EIDs, the attenuation is dominated by the highest energies present in the X-ray tube spectrum. This affects the contrast-to-noise ratio (CNR), since the contrast between different materials is enhanced at low X-ray energies. Conversely, PCDs uniformly weight all photons and can provide a better signal to lower-energy photons, allowing for the improved signal of those substances that are highly attenuating at low energies, such as iodine and calcium, and the optimal CNR ,11,12,13The reduced electronic noise and the enhanced CNR and visualization of small objects contribute to the improvement of the dose efficiency ,15, promIn addition to the weighting of energy, the other primary mechanism for employing the energy information from spectral PCCT data is material decomposition. The application of algorithms for material decomposition from a number of energy-selective images generates a set of basis image maps. The number of bases depends on the number of spectral data  and can be increased to N+1 by imposing mass or volume conservation constraints, which, if not correct, can cause inaccuracies . Each baAnother important benefit of PCCT is the reduction of common image artifacts. The elimination of the electronic noise allows for a marked reduction of the streak and shading artifacts . The conPulmonary vascular diseases encompass a broad and heterogeneous group of conditions including acute and chronic pulmonary thromboembolism, pulmonary hypertension, congenital abnormalities, and inflammatory vasculitis.Pulmonary embolism (PE), that is the blockage of one of the pulmonary arteries caused by thromboembolic material, is associated with high morbidity and mortality .Multi-detector computed tomography permits the rapid accurate exclusion and diagnosis of PE and has become the imaging modality of choice for these purposes ,54. DualIn the study from Kopp et al., a custom-made lung phantom and a rabbit lung were imaged with a preclinical PCCT and a conventional CT in standard and high-resolution (HR-CT) modes . AccordiHagen et al. scanned one hundred consecutive oncologic patients with both PCCT and DECT and demonstrated that the radiation dose for the contrast-enhanced chest CT could be remarkably decreased (43% dose reduction based on size-specific dose estimates) with PCCT without scarifying the image quality. Combining the measurements of pulmonary vessels and the aorta resulted in a significantly higher CNR for PCCT compared to DECT .The improved performance of PCCT may open the doors for a better detection and quantification of the changes in the proximal and distal pulmonary vascular tree. The accurate monitoring of the distal pulmonary vascular involvement is of particular interest in the setting of the chronic thromboembolic pulmonary hypertension (CTEPH) and of coronavirus disease 2019 (COVID-19). CTEPH, currently classified as a group 4 pulmonary hypertension (PH), is a rare but progressive disease, requiring timely diagnosis and treatment . CTEPH iA study performed on 60 patients showed that a gadolinium chelate could be used as an alternative contrast agent for the CT examination of the pulmonary vasculature in patients for whom the administration of iodinated contrast material is contraindicated. The vascular enhancement was good/excellent and provided diagnostic information in 92% of the patients . HoweverThe accurate and robust definition of hepatic vascular structures, known as liver vessel segmentation, is critical for the diagnosis and the radio-frequency ablation and surgical treatments of liver diseases , and plaSi-Mohamed et al., evaluated in vivo in adult rats the capability of PCCT with high spatial resolution to discriminate between two contrast agents: gadolinium and iodine, which were administered simultaneously, one with an intraperitoneal injection and the other one with intravenous injections . A clearThe endovascular aneurysm repair (EVAR) with a stent graft represents a valid alternative to open surgery for the treatment of abdominal aortic aneurysms ,71. HoweSigovan et al., demonstrated the ability of PCCT to improve vascular imaging in the presence of metallic stents . Stents The study of Higashigaito et al. was the first to assess the quality of contrast-enhanced abdominal PCCT acquired in a clinical setting . Thirty-A PCCT angiography of abdominal aorta is displayed in Volume-rendered CTA has become the key modality for the non-invasive assessment of conditions affecting the renal vasculature, including both arterial disorders such as renal artery stenosis, renal artery aneurysms, and dissection, as well as venous disorders such as thrombosis, splenorenal shunts, and intravascular tumor extension . MoreoveThe inherent advantages of PCCT could be particularly beneficial also in the evaluation of the renal vasculature. First of all, the enabled dose-efficient high-spatial-resolution imaging may impact several diagnostic pathways, such as the detection of renal artery stenosis (RAS) in children. Indeed, the decreased caliber of the renal arteries in children compared to adults and the frequent second- and third-order branch stenosis may affect the utility and performance of CTA in the diagnosis of pediatric RSA . OtherwiAnother high-impact clinical benefit of PCCT is represented by its multi-energy capability. In RAS, as well as in coronary artery disease, the fibrous tissue is the most prominent plaque composition, followed by fibro-fatty, necrotic core, and dense calcium tissue . The absPeripheral artery disease (PAD) is the partial or complete obstruction of any part of the peripheral arterial tree, mainly caused by arteriosclerosis . CTA is PCCT, with its intrinsic possibility of reducing blooming by means of improved spatial resolution and material decomposition, may allow for a more detailed and non-invasive characterization of PAD. Li et al., developed a method for quantifying the percent area of stenosis based on the material decomposition of dual-energy and multiple-energy CT images, without the need of segmentation . The abiA recent review highlighted as the combination of ultra-high-resolution CT (UHRCT) with advanced post-processing techniques, such as subtraction techniques, has allowed us to reduce the impact of calcium blooming . HoweverAt present, there is no systematic study demonstrating in vivo the performance of PCCT for noninvasive imaging and the treatment planning of peripheral arterial disease.The key benefits of PCCT, such as improved spatial resolution, signal and contrast behavior, significant noise reduction, dose efficiency, and multi-energy capability, may provide the opportunity to further enhance the diagnostic and prognostic value of CTA. In any case, more extensive research is needed to demonstrate how the theoretical and proven advantages of PCDs can be transferred into clinical practice.


Illegal gold mining has expanded significantly in the Amazon over the past decade,with an average increase of 7.9% per year. According to data from the 37-yearhistorical series of MapBiomas Collection 7, Brazil’s Legal Amazon covers more than90% of the mining area in Brazil, and around 12% of the degraded area is IndigenousLands. In the last 10 years, the area degraded by mining on Indigenous Landsincreased by 400%, totaling more than 18,000 hectares, concentrated mainly (90%) inthree territories: Kayapo, Munduruku, and Yanomami This expansion was driven by the sharp rise in the price of gold on internationalmarkets after the 2008 crisis, the lack of transparency in the production chain andregulatory failures that allow fraud in the declaration of origin of illegallyextracted metal, and the weakening of environmental policies and political pressureto revise mining regulations in indigenous territories, led by the governments offormers Presidents Michel Temer (2016-2018) and Jair Bolsonaro (2019-2022).The Yanomami case has shown that the impacts of mining go far beyond the effectsobserved in the biophysical environment, such as deforestation and contamination ofsoil and water resources. The increase in cases of infectious diseases at locallevel, especially malaria, the intensification of conflicts, and the rise inviolence rates also reflect the expansion of the activity Moreover, the harmful effects of illegal mining also go beyond the boundaries ofindigenous territories, reaching neighboring municipalities. For example, thenegative impacts of mining in the three aforementioned Indigenous Lands affect apopulation of almost 500,000 individuals  A study by Oviedo & Araújo The SPI represents the ability of a municipality to meet the basic needs of itscitizens, providing the conditions to improve quality of life and environmentalsustainability. The results of the aforementioned study show that the municipalitiesaffected by mining have a worse social progress compared with most municipalities inthe Amazon, where the average index is already lower compared with other regions ofBrazil. The situation is even more critical among the 10 municipalities with theIndigenous Lands most affected by mining .Some representatives of the Brazilian National Congress and the private sector arguethat mining on Indigenous Lands is necessary for the regional development of theAmazon. However, this thesis is not based on solid evidence, quite the opposite.Thus, in line with the study by Oviedo & Araújo Therefore, stopping illegal mining on Indigenous Lands in the short term isessential. This measure would be favorable for both the protection of Indigenouspeoples and the social progress of municipalities with this type ofsocio-environmental degradation, since, firstly, mining causes unnecessary publicexpenditure, which could be invested in real improvements in basic services. Theexpansion of the area degraded by illegal mining, besides increasing thesocio-environmental impacts, produces enormous expenses for the health system,public security, social assistance, and environmental inspection Federal Constitution states that:“The lands traditionally occupied by Indians are intended for theirpermanent possession and they shall have the exclusive usufruct of the riches ofthe soil, the rivers and the lakes existing therein”. Any legislativeproposal to allow mining activities on Indigenous Lands inverts the order ofpriorities and makes exceptions the order of business.Article 231 of the Brazilian However, the dynamic of invasions and illegal mining on Indigenous Lands, which hasgrown in recent years, remains Specific actions in the Indigenous Lands most affected by mining should be includedin the new Action Plan for Deforestation Prevention and Control in the Legal Amazon(PPCDAm), announced in June 2023 by the Brazilian Ministry of Environment. Amongthem, we highlight:(i) Implementing and maintaining ethno-environmental protection bases as territorialcontrol posts and logistical support bases for coordinated operations among theBrazilian Federal Police, the Federal Prosecution Office, the Brazilian Army, FUNAI,the Brazilian Institute of Environment and Renewable Natural Resources (IBAMA), andother relevant bodies to combat illegal mining and other illegal activities.(ii) Promoting regular operations to destroy clandestine infrastructure and miningsupport equipment, as well as the immediate expulsion of invaders.(iii) Blocking the logistics of mining support by river, air, or land, by controllingthe rivers that give access to indigenous territories, increasing the strictness ofairspace control, destroying clandestine airstrips, and expanding road inspectionsto seize illegal transportation of fuel, mercury, and illegal timber.Decree n. 9,470/2018(iv) Promoting strict monitoring of the import, sale, transportation, and use ofmercury, in accordance with the terms of the Minamata Convention on Mercury, enactedin Brazil by (v) Updating the normative regulations on the supervision of licensed gold mines inthe Amazon and the gold trade, to make them stricter and more effective incontrolling fraud in the marketing of illegally extracted gold.(vi) Immediately cancel all mining processes, registered with the Brazilian NationalMining Agency (ANM), on Indigenous Lands, including Indigenous territories that arestill in the process of demarcation.(vii) Including equipment and machinery used in mining, deforestation, and selectivelogging activities (such as backhoes and chainsaws) on the Federal TechnicalRegistry list, with a licensing and control mechanism by IBAMA.(viii) Developing safe mechanisms so that Indigenous leaders can be constantlycontacted and consulted in order to contribute to broad knowledge and action in themonitored areas.Indigenous communities affected by mining are often fragile and have manydifficulties in entering the formal economy in a dignified way. Indigenous peopleshardly participate equally in the hegemonic economy, since they are seen as meresuppliers of raw materials and cheap labor. The concept of the bioeconomy is still adisputed territory and an approach under construction, since it promotes thetransition from the current economy, which has waged war on nature, to anotherparadigm of relationship with nature Thus, the standardization of indigenous peoples’ traditional agricultural systemsmust be guaranteed as practices for maintaining biodiversity and combating illegalactivities. These systems provide benefits associated with: (i) production ofsociobiodiversity products and services ; (ii) territorialmanagement practices and biodiversity monitoring; and (iii) promotion andtransmission of Indigenous peoples’ knowledge and cultures.Decree n. 7,747/2012Strengthening this bioeconomy as an antidote to illegal mining requires theformulation of new fiscal, tax, and financial instruments and mechanisms to makesociobiodiversity product chains viable. Existing programs such as the BrazilianNational School Feeding Program (PNAE) and the Food Acquisition Program (PAA) areessential to promote traditional agricultural systems, but they need to be adjustedto increase the acquisition of sociobiodiversity products and broaden access forindigenous peoples. For example, measures to adjust the registration of Indigenousindividuals and associations, simplify public procurement calls, and allocate budgetto agencies for the purchase of products from indigenous peoples and traditionalpopulations are still needed. Moreover, in 2023, the Brazilian National Policy forTerritorial and Environmental Management of Indigenous Lands (PNGATI), regulated byThe available data shows that environmental degradation caused by illegal mining onIndigenous Lands continues to be high, despite all the warnings and the evidencethat this activity does not promote local development. This scenario requirescoordination between local and regional policies, strengthening environmentalmonitoring, promoting chains of sociobiodiversity products, and expandinginternational mechanisms to increase the traceability of production chains, withcertification schemes to curb illegal mining.Indigenous Lands are essential for the physical and sociocultural reproduction ofindigenous peoples and for the exercise of their collective rights. The benefits andservices provided by these territories to the climate are undeniable. The right toIndigenous Lands is the central element of constitutional protection. Thefundamental rights of indigenous peoples will only be fully guaranteed to the extentthat they can combat the socio-environmental impacts on their territories and decideon the essential conditions for their continuity, as they are groups with specificidentities and an inseparable part of the Brazilian nation.2 stocks, water, pollination, etc.Recognizing these contributions and services with appropriate public policies isessential to strengthen sociobiodiversity economies and curb the advance ofpredatory or illegal activities on Indigenous Lands, such as mining, creatingmechanisms to promote and value local ways of life in a win-win scenario.Sociobiodiversity product chains are linked to traditional production systems thatcontribute to the maintenance of landscapes with a very low environmental impact.These practices enable not only greater socio-ecological diversification, but alsothe continued provision of fundamental ecosystem services for society, such asbiodiversity, maintenance of CO


Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-related death worldwide. Conventional treatments for HCC include drugs, radiation, and surgery. Despite the unremitting efforts of researchers, the curative effect of HCC has been greatly improved, but because HCC is often found in the middle and late stages, the curative effect is still not satisfactory, and the 5-year survival rate is still low. Nanomedicine is a potential subject, which has been applied to the treatment of HCC and has achieved promising results. Here, we summarized the factors affecting the efficacy of drugs in HCC treatment and the strategies for improving the efficacy of nanotechnology-based drugs in HCC, reviewed the recent applications’ progress on nanotechnology-based drugs in HCC treatment, and discussed the future perspectives and challenges of nanotechnology-based drugs in HCC treatment. China has the largest population of hepatocellular carcinoma (HCC) in the world and most HCC patients are already in the advanced stage when diagnosed . The proin vitro (IVT) could be used for vaccine mass production due to its simple and fast reaction  drug nanoassemblies, which promote the formation of 3D intramolecular and/or intermolecular structures to block intramolecular cleavage sites . For exaCoupling technology is widely used in nanomedicine. This conjugated approach enhances the targeting specificity of drugs by directly covalently binding different components, including lipids, peptides, aptamers, antibodies, and sugars . One of in vivo environment is relatively complex, such as the mutation or loss of antigens or ligands caused by tumor gene mutation, and the change of antigen conformation on tumor surface influenced by TME, which reduces the targeting of nanotechnology-based drugs. More preclinical data are needed to promote the progress of clinical applications. In addition, some nanoparticles also respond to external stimuli such as ultrasonic stimulation, heat, pH, and light, and these types of nanoparticles could release drugs in a controlled manner, thereby improving the precision and targeting of drug delivery  and radiofrequency ablation (RFA). Using the reactivity of nanoparticles to external stimuli such as ultrasound and heat, the combination of interventional therapy and these properties forms interventional nanotherapeutics. The nano-drug delivery system could improve the targeting and stability of chemotherapy drugs in TACE and improve the efficacy of anti-HCC . TACE coThe gas levels of the tumor microenvironment are different from those of normal tissue. Therefore, the specific characteristics are an ideal endogenous treatment strategy. For instance, NanoNO can sustainably release and effectively deliver NO gas to HCC cells to normalize HCC vasculature . Gas theRadiotherapy is a palliative therapy to improve the quality of life of patients with advanced HCC, and it is mainly used in combination with other therapies. In the nanotechnology of HCC treatment, the development of nano-radiosensitizer is the main. Xiao et al. found that targeted nano self-assembled Pt STNA containing platinum drugs can enhance ROS levels in HCC cells under X-ray irradiation and thus synergistically play the role of radiosensitizer and chemotherapy .Photodynamic/sonodynamic/photothermal therapy (PDT/SDT/PTT) is a new therapy in the treatment of HCC for its advantages of being non-invasive and accurate. Photodynamic therapy mainly uses a specific wavelength of laser irradiation to stimulate the photosensitizer absorbed by the tissue, resulting in cytotoxic effects. Sonodynamic therapy uses ultrasound to penetrate biological tissues, especially focused ultrasound can focus sound energy on deep tissues without trauma, and activate some sound-sensitive drugs (such as hematoporphyrin) to produce anti-tumor effects. PTT is a new tumor treatment method, which is to inject nanoparticles into tumor tissue, and then use laser irradiation of nanoparticles to produce photothermal effect, thereby killing tumor cells. Copper sulfide nanoparticles coated with hybrid film have a photothermal conversion effect under near-infrared irradiation, which can be used for photothermal therapy of HCC . At presCombining the advantages of nanodelivery systems allows for the combination of multiple HCC therapies to maximize efficacy and reduce the toxic side effects of monotherapies. Radiosensitization and PDT/SDT/PTT mentioned above are often combined with other treatments. The iridium-based photosensitizer is combined with sorafenib (IPS) in the form of self-assembly. Under the action of 532 nm laser, the uptake of this particle by HCC cells is increased, and the intracellular ROS is increased to enhance the anti-HCC effect . In addiHere, we reviewed strategies for improving the efficacy of HCC drugs with nano-delivery systems and their applications in HCC treatment. Nanoparticles can protect drugs from degradation and improve their targeting to improve the efficiency of HCC treatment. At present, nanodrug delivery systems show great potential in the treatment of HCC, especially immunotherapy, because they can effectively enhance the immune response. However, the regulatory effect of nanoparticles on tumor immune cells, such as tumor-associated neutrophils, has not been fully clarified, and these cells are key to improving HCC immunotherapy, requiring further efforts by researchers.in vivo, such as off-target effects of mRNA vaccines loaded with lipid nanoparticles, even when an intramuscular injection is performed (In addition, there are still some problems that need to be solved in the treatment of HCC. First, there is a need for better research on whether the nanoparticles and their formulations cause unnecessary immune responses and toxic side effects erformed . Therefoerformed . In conc


Anti NMDAR encephalitis is a relatively common autoimmune encephalitis characterized by complex neuropsychiatric features and the presence of Immunoglobulin G antibodies against the NR1 subunit of the NMDA receptors in the central nervous system. It causes psychiatric features, confusion, memory loss and seizures followed by a movement disorder, loss of consciousness and changes in blood pressure, heart rate and temperature. Postpartum depression symptoms usually develop within the first few weeks after giving birth , but may begin earlier/during pregnancy / or later /up to a year after birth. They include: inability to sleep or sleeping too much, depressed mood or severe mood swing, difficulty bonding with your baby, withdrawing from family and friends, fatigue or loss of energy, feelings of shame, guilt or inadequacy, diminished ability to think clearly, concentrate or make decisions, anxiety and panic attacks, thoughts of harming yourself or your baby. Untreated may last for many months or longer.Recent studies have highlighted the possibility that a subset of patients with first-onset severe psychiatric episodes might suffer from undiagnosed autoimmune encephalitis. The acute onset of severe atypical psychiatric symptoms in young female patients should raise the index of suspicion for anti-NMDA receptor encephalitis, particularly in the setting of neurological symptoms, including side effects of antipsychotic treatment.//Creating a therapeutic environment is an interdisciplinary clinical and theoretical approach to psychiatric treatment in hospital settings, the basic idea of which is that the entire environment has therapeutic potential. Psychodinamic knowledge and understanding of the process as well as principles of body-oriented psychotherapy may be of great importance in the treatment of these patients in addition to the use of pharmacotherapy.None Declared


In this review, we provide a general overview of the current panorama of mining strategies for multi-omics data to investigate lncRNAs with an actual or potential role as biological markers in cancer. Several multi-omics studies focusing on lncRNAs have been performed in the past with varying scopes. Nevertheless, many questions remain regarding the pragmatic application of different molecular technologies and bioinformatics algorithms for mining multi-omics data. Here, we attempt to address some of the less discussed aspects of the practical applications using different study designs for incorporating bioinformatics and statistical analyses of multi-omics data. Finally, we discuss the potential improvements and new paradigms aimed at unraveling the role and utility of lncRNAs in cancer and their potential use as molecular markers for cancer diagnosis and outcome prediction. The advent of next-generation sequencing and other revolutionary technologies for the study of omics, such as genomics, transcriptomics, proteomics, and metabolomics, has completely transformed the way basic and clinical cancer research is conducted ,2. As a In this review we do not intend to cover an exhaustive compendium of the many lncRNAs and their biological and molecular roles in cancer, nor of the large number of bioinformatics programs that have been developed for the analysis of transcriptomics, genomics, and epigenomics data, both of which have been extensively discussed elsewhere ,22,23,24The complexity of genomic alterations, gene expression, protein–protein interactions, epigenetic mechanisms, cellular secretome, and metabolome is a complex subject, especially when we want to define how their components interact . For thiCancer is characterized by the somatic acquisition of various cellular alterations that lead to selective advantages, such as unrestricted growth, the suppression of apoptosis, and enhanced metabolism , and genFrom an omics and bioinformatics point of view, we can broadly classify the approaches that have been developed to prioritize lncRNAs with a possible association with cancer into at least two categories: (1) an early integrative analysis of somatic variants with cancer driver potential that have an impact on the functional activity of lncRNAs associated with prognosis in cancer patients ,69,70,71The complexity of cancer genomes goes beyond a set of specific targetable driver mutations. Other features, such as the tumor mutational burden (TMB) and mutational signatures, are increasingly being incorporated into bioinformatic analyses aimed at uncovering therapeutic and prognostic insights in cancer . TherefoThe number of studies discussed so far provided a vision of different modalities of integrative multi-omics analyses being employed as powerful strategies for identifying and characterizing lncRNAs as informative features that allow for diagnosis, prediction, and prognosis. Without an integrative genomic approach, it is unlikely that more complex questions can be addressed, for example, the search for the interaction of lncRNAs with other biological and environmental factors, such as sex hormones, smoking, occupational risk, and dietary habits, among others, and their association with the risk of cancer development, patient survival, and response to treatment. For instance, lung adenocarcinoma (LADC), the most common type of lung cancer, is largely caused by chronic tobacco smoking. However, approximately 25% of cases occur in non-smokers. Notably, this proportion of LADC in non-smokers is associated with being female, and the etiology remains an elusive question. In a recent study to uncover genomic evidence of smoking-associated mutagenesis, researchers performed a multilevel integrative analysis using whole-genome sequencing and RNA-seq data to unravel the mutational processes and complex genomic rearrangements that drive the development of LADC. One of the intriguing findings of this multi-omics analysis was the discovery of a recurrent fusion gene, composed of the gene ERBB3 and the lncRNA anti-estrogen-resistance 4 (BCAR4), which was present in two tumors from female cases in which low to no contribution of a mutational signature associated with direct DNA damage caused by tobacco smoke mutagens (COSMIC signature 4) was observed  Figure . RecentlIndeed, genomics and mathematical analyses of the patterns of somatic alterations have become a powerful strategy for identifying cancer driver genes. In this regard, although somatic point mutations and small insertions and deletions (INDELs) have been the primary focus of cancer genomic studies, copy-number alterations (CNAs) are also important forms of DNA aberrations, also referred to as somatic copy-number alterations (SCNAs), which encompass larger genomic regions and often harbor key genes involved in the development and progression of many cancers ,82 Figu. Not surA second consideration that arose in light of the above approaches for understanding the actual contribution of lncRNAs as drivers of cancer and its deregulation was based on estimating the relationship that exists between the copy-number values of the SCNAs at the lncRNA loci and the expression levels of their corresponding transcripts present in a given cancer type. Indeed, this aspect was consistent with our knowledge that the differential gene expressions of the protein-coding cancer driver genes were significantly correlated with the CNAs ,91. As aCancer is a heterogeneous disease that includes a diversity of tumors from the same or different organs and tissues, displaying differences in cellular compositions and biological and molecular features . Much ofThere is increasing evidence that large numbers of lncRNAs are present in the human genome. The latest release of LNCipedia, a public database for lncRNA sequences and annotation, contains 107,039 high-confidence transcripts that show no coding potential belonging to 49,372 lncRNA genes . UndoubtAs discussed above, the technological and computational advances in recent decades have allowed for the identification of thousands of lncRNAs whose molecular alterations are associated with various types of cancer . A majorDespite intense research into the mechanisms underlying altered lncRNAs, our understanding of the global biological impact of lncRNA regulation in tumors remains limited . It is cIn this section, we will review the progress made in understanding the multi-omics biological features through machine learning and artificial intelligence approaches and provide an overview of the recent advances in uncovering the regulatory basis underlying the functionalities of lncRNAs at various molecular and cellular biological levels.Apart from a few well-known lncRNAs, the landscape of cancer lncRNAs is far from complete. The diverse functional repertoire of lncRNAs in cancer can be explored through (1) their function as driver genes, resulting from early mutations that are positively selected during tumorigenesis, or (2) as downstream genes, resulting from non-genetic changes in their expression, localization, or molecular interactions . AlthougOne of the first statistical methods for driver gene discovery was OncodriveFML , which iAnother integrative method for predicting lncRNA drivers that are relevant to tumorigenesis is ExInAtor, which identifies genes with a high somatic single nucleotide variant load across the tumor genomes using the DNA mutation patterns  and expression data as proxies for their functionality. ExInAtor was modeled on 1112 whole genomes from 23 cancer types deposited in GENCODE, and predicted 15 lncRNA drivers with a high confidence, of which nine were novel lncRNAs and six were known cancer-related transcripts, including PCA3, MALAT1, BCAR4, lncRNA-ATB, and SAMMSON. Most of these lncRNAs were tumor-specific, although NEAT1 and MALAT1 were identified in a pan-cancer context, confirming their role in tumorigenesis. The set of previously unreported driver lncRNAs include MIR100HG, AP000469.2, RP11-308N19.1, RP11-455B3.1, RP11-332J15.1, RP11-707A18.1, RP11-6c14.1, RP11-1101K5.1, RP11-354A14.1, and RP11-189E14.4. These novel candidates are evolutionarily conserved, expressed in normal tissues, and have an increased gene length. They also tend to be proximal to cancer SNPs and are encoded in CNA regions, suggesting a role in tumorigenesis. The authors highlighted MIR100HG, which was highly conserved and had canonical histone modifications in the promoter region and transcription factor binding sites [More recently, to enhance the discovery of cancer-related lncRNAs and gain insight into their biology, the Cancer lncRNA Census (CLC) was presented as a tool to provide functional or genetic evidence of lncRNAs roles in cancer by integrating genomic and transcriptomic data associated with cancer in different mammalian species . To dateThe integration of DNA, RNA, and protein alterations and the way they cooperatively interact provide new evidence for identifying dysregulated lncRNA in cancer. For example, LongHorn , a recenAn interesting approach presented by Mitra and collaborators for predicting the biological dependencies of uncharacterized lncRNAs focused on the identification of co-essential modules by integrating the copy number, and epigenetic and transcriptomic data of the lncRNA landscape from exogenous knockouts or activation screens that were generated using CRISPR techniques . By applAlthough DNA methylation dysregulation is associated with cancer, the molecular mechanisms of how methylation and transcriptional lncRNA patterns are reciprocally modulated in cancer remain largely unknown. A novel integrative analysis framework, called MeLncTRN , integrates transcriptome, DNA methylome, and copy-number variation profiles to identify the regulatory circuits driven by epigenetically driven lncRNAs across 18 cancer types . An analEmerging evidence has also revealed the underlying crosstalk between lncRNA and genomic instability, a relevant hallmark of cancer. Novel approaches integrating chip-seq, WGS, and WES data revealed an unexpected relationship between oncogenic lncRNAs and epigenetic alterations that contribute to chromosome fragility in cancer. To characterize the lncRNA-based mechanism by which aberrant epigenetic signatures can be generated, the authors used as a conceptual, the sub-telomeric chromosomal locus 8q24, which contains the cMYC gene and a large histone domain H3 (CENP-A) variant, both of which were altered in cancer cells of various solid tumors. This region also encoded five unique lncRNAs sequences, namely PCAT1, PCAT2, CCAT1, CCAT2, and PVT1, which negatively modulated the occupancy of CENP-A at the chromosomal locus. Their results indicated a competition between the lncRNAs transcription and R-loop occupancy that strongly contributed to the maintenance of CENP-A invasion, which ultimately affected the chromosome stability .An oncology milestone that was already mentioned is the TMB, which is related to the infiltration of various immune cell populations that can enhance or limit cancer programs . RecentlIn this section, we provide a summary of the approaches we took to address biological data integration and discuss the pitfalls of overcoming and optimizing the use of data from multiple sources and technologies in an analysis pipeline. A first challenge was the difference between the samples, replicates, and technology used, which favored batch effects. Additionally, the different modalities for measuring the cell levels with different measurements posed a significant computational challenge, as there was no common virtual space to integrate the samples.Machine learning methods have been increasingly used in attempts to better understand the biology of molecules, such as lncRNAs. These methods can be generally classified into supervised and unsupervised learning. The former includes dimension reduction and clustering, while the latter includes regression and classification. In the context of the lncRNA landscape, one of the challenges that has arisen is the accurate identification of true lncRNAs from other types of RNAs, along with the definition of their biological roles. The main approach for the identification of lncRNAs is based on their coding potential and length. Later, other features were integrated, such as the presence of an open reading frame (ORF), nucleotide composition, kmers, secondary structure, codon usage, ribosome release score, conservation scores, and others. Among the most used algorithms for data integration are logistic regression, random forest (RF), support vector machine (SVM), and deep learning . From a In recent years, a number of strategies based on the use of deep learning and complex network analyses have emerged to uncover the relevant dysregulations of lncRNAs and their potential value in identifying their relationships with cancer diagnosis, prognosis, and treatment ,126,127.In addition, all the data have different calculation rules, which can lead to inaccuracies. Moreover, the link between lncRNAs and cancer goes beyond identifying the molecules that may be actively involved in the disease. Other aspects have been explored, such as the identification of biomarkers that are capable of predicting prognosis or even a response to drugs ,131. ForIn general, the methods for lncRNA identification, the prediction of their functions, and their relationship to disease, even as part of precision medicine tools for prognosis and drug response prediction, continue to improve by using higher level features and generating more and new information to feed the algorithms for better classifications. Despite these efforts, the integration of all the available information in a biologically meaningful way remains a challenge. During biological analysis, and more specifically in omics data analysis, subsequent functional validation steps are essential to provide new, more complete, and useful insights for future applications that can be transferred to the clinic. Thus, designs should include a holistic view integrating computational and experimental characterization.What is the best way to answer new questions and discover the novel and controversial mechanisms of lncRNAs in a disease state through multidimensional analysis? A good example is the milestone discovery that lncRNAs are completely unable to produce peptides, even though there is evidence that some lncRNAs are found in the cytoplasm and can associate with ribosomes, suggesting the possibility of translation and the production of microproteins .Unlike other protein by-products, such as insulin, which are derived from larger proteins, microproteins are small and translated directly from short open reading frames (sORFs) of less than 300 nucleotides that produce a protein of up to 100 amino acids. These sORFs are often found within the lncRNAs sequence. Despite the difficulties, researchers are making progress in characterizing the functions of the microproteins generated by lncRNAs that are altered in cancer and are related to the clinical behavior of tumors ,136,137.Although the complete repertoire of functional sORFs is unknown, new techniques and computational approaches are being developed based on the search for conserved DNA sequences, natural selection, ancient phylogenetic origins, and ribosomal profiling—a tool based on deep sequencing that allows for detailed measurements of translation ,139,140.The field of lncRNA research has developed rapidly over the past decade, moving from understanding their basic biological properties to exploiting their clinical relevance. As a result, lncRNAs have been proposed as biomarkers and therapeutic targets that are being actively explored. In this section, we review the emerging strategies for the therapeutic exploitation of lncRNA.It would be appropriate to begin by discussing the value of circulating lncRNAs as biomedical tools for the detection and monitoring of various diseases. Despite the important progress in translating the clinical utility of circulating molecules as biomarkers, such as proteins, metabolites, or free mRNA, there are still relevant limitations. This is why the study of lncRNA has been postulated as a new source of biological information that presents relevant advantages over other circulating analytes, such as a greater resistance to degradation, stability in biofluids due to their secondary structures, and their transport in extracellular vesicles. These characteristics present them as reliable cancer biomarkers ,149.The case of PCA3 is a good example to illustrate the potential use of lncRNAs as informative biomarkers in cancer clinics. In 1999, Bussemakers and colleagues discovered that the ncRNA prostate cancer antigen 3 (PCA3), which they initially named differential display code 3 (DD3), was overexpressed in prostate cancer tissues compared to non-neoplastic prostate tissues . InteresA rapidly growing area of interest in the field of oncology is the phenomenon of drug resistance, which is the major limiting factor in achieving a cure for cancer patients. Emerging preclinical evidence supports that the lncRNA expression patterns predict a response to anticancer drugs ,152. By Given that lncRNAs can act as competitive endogenous RNAs , they could potentially control resistance-related biological processes. By constructing a ceRNA network, including lncRNA and mRNA, several drug resistance-related modules were identified as novel drug resistance markers. For example, the GAS5-RPL8 ceRNA pair regulated the drug resistance, as the GAS5 down-expression enhanced the RPL8 miRNA inhibition, which was reported to be associated with chemotherapy resistance . The intThe therapeutic targeting of non-coding RNAs is an attractive approach for the treatment of cancer. Although no lncRNA-based therapy has been introduced into clinics, the functional diversity of lncRNAs provides an opportunity for their therapeutic modulation through transcriptional and post-transcriptional inhibition, the steric hindrance of promoters or secondary structures, exogenous synthetic lncRNAs, and editing tools such as CRISPR-Cas systems ,156,157.With the advent of new technological resources, such as single-cell and spatial genomics and transcriptomics and the popularization of and ease of access to machine learning frameworks, multi-omics data integration approaches will further establish themselves as a powerful paradigm in the study of lncRNAs in cancer. The current state of knowledge includes a variety of studies and reviews that offer different perspectives on the topic. These range from studies that focus on elucidating the biological role of lncRNAs in cancer, to their proposed utility as molecular markers in clinical cancer research and the revision of computational methods for predicting lncRNA interactions with other molecules. However, many questions remain regarding the pragmatic application of the different molecular technologies and bioinformatics algorithms for mining multi-omics data. Furthermore, there is no clear consensus on how to integrate the different omics platforms and what information can be obtained from such approaches that can be used for the biological and pathological characterization of lncRNAs. Although many papers in the literature claim to have discovered the biological role or association between different lncRNAs and cancer using multi-omics strategies, only a fraction of them integrated information from different molecular platforms. Others explored different aspects of the same molecular features interrogated by each platform , DNA somatic mutations, copy-number variations (CNV), or DNA methylation). In this review, we referred to multi-omics as the paradigm of using data obtained from and including two or more of the aforementioned molecular features. There is little doubt that these methods will complement our set of resources to unravel the relationships between lncRNAs and other biological factors that critically modulate cancer cell fitness and demonstrate new resources for studying tumor-relevant lncRNAs using dedicated multi-omics computational tools. It is highly desirable that, in the foreseeable future, researchers make efforts to become native users of these technologies to keep up with the current and future challenges in the field of cancer lncRNAs.A crucial step in the study of lncRNAs as disease markers from a statistical point of view is the validation of their performance as predictors. However, there is still vague information and discrepancies about the biostatistical and machine learning approaches that have been used to discover and evaluate the performance of lncRNAs signatures, the power of these approaches, and the recall and sensitivity they report. In this regard, it is in the best interest of the entire research community to reach a consensus on the best practices for producing a more robust statistical model and description of the many steps in the selection of these models and validation methods. For example, the studies that used feature selection strategies to select lncRNAs as the variables of interest followed by the use of univariable or multi-variable regression models  should provide additional rationales for the chosen method. In order to increase the scientific validity of statistical or machine learning approaches based on multi-omics data, it is important that researchers ensure the reproducibility of their findings by incorporating cross-validation information, which would give researchers a clearer perspective on the bias and general application of such models.As the pace of technological advancement accelerates, an even greater amount of data will be generated from which researchers can extract novel features to describe the biological, physiological, and pharmacological properties of lncRNAs. Perhaps the two most notorious state-of-the-art paradigms in transcriptomic analysis are single-cell and spatial RNA-seq technologies, which seek to explore the repertoire of RNA molecules and their differential expressions at a single cell level and histological coordinates. Beyond the obvious cost of computational resources, this scenario comes at the expense of simple modeling, as incorporating these data into our research will add new layers of complexity. In this context, the lack of parsimony could become a more latent risk when generating new models explaining the associations between lncRNAs and different cancer hallmarks and their observable pathophysiological consequences . By integrating single-cell and spatial transcriptomics data into multi-omics frameworks, researchers would be able to obtain new features such as the proportion and identity of cells within a given tumor that express a particular lncRNA. Even more, these data could be used to refine the association of lncRNA molecules with features such as the TMB, which is currently of value in cancer prognosis, the proportion of specialized cells harboring a somatic aberration in a locus containing functional lncRNAs, or the specific wiring of epigenomics interactions and signals in which lncRNAs are involved within such a cell. From a clinical point of view, having these features as the predictor variables associated with a particular outcome could indeed make the modeling process more demanding and complex, with the risk of overfitting. However, this risk can be mitigated if the precautions mentioned in the previous paragraphs are taken into account. Ultimately, the addition of these new dimensions could enhance the potential use of lncRNAs as diagnostic, prognostic, and predictive factors with more objective real-world applications in cancer clinics.


Coronary microvascular disease (CMVD) is a high risk factor for many cardiovascular events. Due to the limited understanding of its pathophysiological mechanism, modern medicine still lacks therapeutic drugs for CMVD. Existing clinical studies have shown that traditional Chinese medicine (TCM) can effectively improve the clinical symptoms and quality of life of CMVD patients. As an indispensable part of TCM, Chinese patent medicines (CPMs) are widely used in clinical practice. In the face of numerous oral CPMs for treatment of CMVD, how to choose a reasonable medication regimen is one of the important issues in clinic. Based on this, this paper reviewed the clinical efficacy and recommended level of 12 CPMs in the treatment of CMVD, which are recommended by expert consensus on diagnosis and treatment of coronary microvascular disease with integrated Chinese and Western medicine (WM). In addition, this study also systematically summarized the possible mechanisms of CPMs in the treatment of CMVD by protecting coronary microvascular endothelial cells, improving vascular endothelial function, inhibiting inflammation, reducing oxidative stress, promoting angiogenesis, and improving hemorheology, aiming to provide meaningful information for its clinical application. Coronary microvascular disease (CMVD) refers to a class of diseases characterized by subjective symptoms and/or objective evidence of myocardial ischemia due to insufficient myocardial blood supply and abnormal regulation of myocardial blood flow caused by the abnormal structure and/or function of coronary microvessels In recent years, the understanding of CMVD is gradually deepening both domestically and internationally. In 2017, academician Zhang Yun and others developed the Chinese Expert Consensus on the Diagnosis and Treatment of CMVD Currently, the progress of WM treatment of CMVD is relatively slow, and there is no drug available for CMVD. Clinical treatment of CMVD is still dominated by traditional cardiovascular drugs such as nicorandil, statins, calcium channel blockers and renin-angiotensin system blockers CMVD is one of the dominant diseases in TCM treatment. CPMs is a modern preparation processed according to the prescribed prescription and preparation technology under the guidance of the TCM theory. Compared with TCM decoction, oral CPMs has the advantages of convenient to carry, controllable dose and good taste, and occupies an important position in the field of medical care in China. At present, there are few high-quality evidence-based clinical studies on the treatment of CMVD with CPMs that meet the requirements, and some outcome indicators have not been fully supported by evidence-based evidence. Moreover, there is a lack of evidence-based suggestions for the diagnosis and treatment of CMVD-integrated TCM and WM. In the face of many oral CPMs for treatment of CMVD, how to choose the reasonable drug regimen is one of the important clinical problems. The Expert Consensus on the Diagnosis and Treatment of CMVD with integrated Chinese and WM is the first expert consensus on the treatment of CMVD with proprietary TCM, and it is extremely important for increasing the efficacy of CMVD treatment by serving as a guide and reference for TCM and WM specialists, general practitioners and primary care physicians According to the different etiologies of CMVD, it can be divided into three categories: CMVD without OCAD, CMVD with OCAD, and other types of CMVD Referring to the 2020 EAPCI Expert Consensus Document on INOCA According to the Chinese Expert Consensus on the Diagnosis and Treatment of CMVDCMVD belongs to the category of TCM “chest obstruction” and “heartache”, which can refer to TCM “chest obstruction” and “heartache” for syndrome differentiation and treatment. The common TCM syndromes of CMVD include blood stasis, phlegm turbidity, qi deficiency, qi stagnation, Yin deficiency, and Yang deficiency. The common complex syndrome type is qi deficiency and blood stasis syndrome, followed by phlegm and blood stasis syndrome, Yang deficiency and blood stasis syndrome, and qi stagnation and blood stasis syndrome Search strategy/methodology: According to the inclusion criteria, literature was retrieved from CNKI, Wanfang Data, VIP Journal database, PubMed, the Cochrane Library, EMbase and other databases from the establishment of the database to May 2022, and supplementary retrieval was conducted by referring to the literature included in the systematic reviews included in this study. The search terms used to define the disease included: coronary microvascular disease, coronary microvascular dysfunction (CMD), microvascular angina, microvascular chest pain, cardiac syndrome X, coronary slow flow phenomenon, coronary slow flow, no-reflow.Inclusion criteria: Subjects: Patients with CMVD, including CMD, microvascular angina (cardiac syndrome X), coronary slow flow phenomenon, and no reflow after PCI. Intervention and control measures: ① The experimental group was treated with a Chinese patent medicine or external treatment of TCM combined with conventional WM, the control group was treated with conventional WM; ② The experimental group was treated with a Chinese patent medicine or external treatment of TCM, the control group was treated with placebo or routine nursing measures. Type of study: Randomized controlled trials (RCTs) or systematic reviews.Exclusion criteria: ①Studies with missing important data such as sample size and outcome measures; ② Studies lack comparability of baseline data between groups.; ③ Repeatedly published studies; ④ Studies for which full-text reports could not be obtained; ⑤ Studies that significantly violate the diagnostic and treatment routine.The clinical evidence for this consensus was constructed by searching the currently published RCTs or systematic reviews of the treatment of CMVD with CPMs.The Expert Consensus on the Diagnosis and Treatment of CMVD with integrated Chinese and WM recommends 12 CPMs for the treatment of CMVD, among which the majority are for the treatment of qi deficiency and blood stasis syndrome, and qi stagnation and blood stasis syndrome, while the treatment of other syndromes of CMVD is insufficient, as shown in Table 3Syndrome differentiation of microvascular angina belongs to qi deficiency and blood stasis syndrome except for the typical symptoms of angina pectoris, there is also shortness of breath and fatigue, and the symptoms are aggravated during activity. Based on the routine treatment of WM, Tongxinluo capsule, Qishen Yiqi dropping pills or Naoxintong capsule (strong recommendation) and Shexiang Tongxin dripping Pills (weak recommendation) can be used for such patients Syndrome differentiation of microvascular angina belongs to qi stagnation and blood stasis syndrome except for typical angina pectoris, at the same time, it can be seen that the pain in the chest and flank is aggravated with the change of mood. Based on the routine treatment of WM, such patients can be treated with Shexiang Baoxin pills, Compound Danshen dripping pills, Wide chest aerosol, Suxiao Jiuxin pills, Xuefu Zhuyu capsule (strong recommendation), and Yindan Xinnaotong soft capsule (weak recommendation). Shexiang Baoxin pills The syndrome differentiation of microvascular angina belongs to the qi and Yin deficiency syndrome. In addition to the typical symptoms of angina pectoris, there are also symptoms of qi deficiency such as fatigue, shortness of breath, aggravation of labor, and Yin deficiency such as tidal fever and sweating, night sweats, and red tongue with little coating. Such patients can be treated with Tongmai Yangxin pills based on conventional WM (strong recommendation). Compared with conventional WM, Tongmai Yangxin pills combined with conventional WM can reduce the positive rate of treadmill exercise for patients with microvascular angina The differentiation of microvascular angina pectoris belongs to the heart blood stasis syndrome with clinical manifestations of chest pain, chest tightness, and lip and/or tongue dark purple can be treated with CPMs for activating blood and resolving stasis, dredging collaterals and relieving pain such as Danshen tablets (weak recommendation). Danshen tablets combined with conventional WM can prolong the duration of treadmill exercise, and reduce the frequency of angina attacks and the dosage of nitroglycerin in the treatment of microvascular angina patients compared with conventional WM For patients needing revascularization, the application of TCM intervention based on conventional WM treatment before surgery can reduce the incidence of patients with no reflow after PCI. Clinical evidence shows that Tongxinluo capsule combined with conventional WM can be used to treat acute myocardial infarction patients and reduce the no-reflow rate (strong recommendation). For patients with ST-elevation acute myocardial infarction (STEMI), combined application of Tongxinluo capsule and conventional WM before emergency PCI further reduced the no-reflow rate within 24h compared with conventional WM In the case of patients with no-reflow after PCI, combined with TCM intervention based on conventional WM treatment can further reduce the no-reflow rate of patients. Clinical studies have shown that Compound Danshen dripping pills combined with conventional WM can be used to improve coronary blood flow in patients with coronary no-reflow after PCI (strong recommendation). For patients with coronary no-reflow after PCI, compared with conventional WM, combined application of Compound Danshen dripping pills based on conventional WM after surgery can reduce the incidence of no-reflow In conclusion, current clinical studies suggest that CPMs can improve IMR and LVEF in CMVD patients, reduce the frequency of angina attacks, shorten the duration of angina, extend the time of treadmill exercise, reduce the dosage of nitroglycerin, improve activity tolerance and quality of life.CMVD is caused by the interaction of multiple factors and mechanisms, including abnormal microvascular function, vascular endothelial dysfunction, inflammatory response, oxidative stress, etc. These physiological and pathological changes play different roles in the occurrence and development of coronary microcirculation Cardiac microvascular endothelial cells (CMECs) play an important role in maintaining the normal function of cardiac microvascular, and the dysfunction of CMEC is often preceded by myocardial injury The vascular endothelium plays an important role in maintaining the normal vascular system. The abnormal coronary vascular endothelial function could cause the occurrence and development of a variety of cardiovascular diseases, thus protecting vascular endothelial function is of great significance for the prevention and treatment of CMVD. Coronary endothelial dysfunction is closely related to the imbalance between vasoconstrictor factor endothelin-1 (ET-1) and diastolic factor nitric oxide (NO) caused by vascular endothelial injury Coronary microvascular endothelial cell injury is the core of CMVD induction. Inflammatory response plays an important role in the occurrence and development of coronary microvascular endothelial dysfunction. Inflammatory factors not only cause vascular endothelial injury and intima thickening but also reduce the synthesis of NO and prostacyclin in endothelial cells, activating immune cells to release human endothelin (ET) and ET immune-like activators, resulting in abnormal endothelial function CMVD is caused by the interaction of multiple factors and multiple mechanisms, among which oxidative stress is considered to be one of the main mechanisms. Under oxidative stress, the production of oxygen free radicals increases, triggering mitochondrial dysfunction, calcium overload, DNA damage, and myocardial membrane lipid peroxidation, which can eventually lead to cell death The decreased number of myocardial capillaries is one of the important determinants of CFR. Angiogenesis can effectively improve CMVD by increasing blood supply capacity, restoring cardiac function, and improving hemodynamics. Zhang et al. Sustained hemodynamic abnormalities can lead to structural damage of microvessels, increased vascular walls permeability, capillary leakage, basement membrane damage and secondary thickening, vascular cavity stenosis or even occlusion, microthrombus formation, microcirculation ischemia, hypoxia, and then lead to organ dysfunction. The hemorheological parameters are closely related to the severity of CAD, and the improvement of various hemorheological parameters such as high viscosity can improve coronary blood flow. Li et al. With the rapid development of evidence-based medicine and coronary interventional techniques, the clinical significance of CMVD has received increasing attention. CMVD has a complex etiology and pathogenesis, its treatment remains limited to improving lifestyle, controlling the traditional risk factors for atherosclerosis, and relieving myocardial ischemia. There are currently no large sample randomized clinical trials using cardiovascular events as the assessed endpoint and CMVD as the study subject. Therefore, it is unclear which therapy option can lower the rate of cardiovascular events in CMVD. And modern medicine still lacks an effective treatment for CMVD.In recent years, the understanding of CMVD in TCM has been considerably advanced, and numerous clinical types of research have been conducted. The available clinical evidence suggests that treatment for CMVD with TCM has been shown to reduce the attack times of angina pectoris, shorten the duration of angina pectoris attacks, prolong the duration of treadmill exercise, reduce the dosage of nitroglycerin, ameliorate TCM syndrome, improve cardiac function, improve exercise tolerance and quality of life, reduce mortality and rehospitalization rates, and improve long-term prognosis, etc. But there is a lack of evidence-based suggestions for the Diagnosis and Treatment of CMVD with integrated Chinese and WM. This paper systematically summarizes the clinical evidence of proprietary TCM for the treatment of coronary microvascular disease recommended by the Expert Consensus on the Diagnosis and Treatment of CMVD with integrated Chinese and WM, however, few high-quality evidence-based clinical studies fit the criteria, and several of the outcome indicators are not yet supported by sufficient evidence-based evidence. The ultimate level of evidence and the severity of the recommendation were impacted by some of the included studies' confusing statements of sample size estimation, random assignment concealment strategies, blinded designs, and shedding rates. Future clinical studies on CMVD treatment with TCM should be conducted in large-sample, multicenter randomized clinical trials with cardiovascular events as the observed endpoint, to test the possibility of developing new drugs and therapies specifically targeting CMVD to improve clinical endpoints and to establish treatments with evidence-based medical evidence. TCM has multi-target and multi-path therapeutic characteristics, and certain results have been achieved so far, as research advances, it is thought that TCM offers enormous potential for CMVD prevention and therapy.


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