•Advanced renal cell carcinoma (aRCC) with sarcomatoid features has a poor prognosis.•Immune checkpoint inhibitors (ICI) are considered standard of care treatment in aRCC.•Clinical trials with ICI ...have included aRCC patients with sarcomatoid features.•The reviewed data suggests a significant benefit with ICI in sarcomatoid tumors.•In aRCC with sarcomatoid features ICI-based therapy should be the preferred regimen.
Advanced or metastasized renal cell carcinoma (mRCC) can present with sarcomatoid features, which is considered a poor prognosis marker and a treatment challenge. Several trials in first line mRCC have included immune checkpoint inhibitors (ICI) in combination either with other ICI or tyrosine kinase inhibitors (TKI), that have led to the approval of some of these treatment strategies and their recommendation in international guidelines. The authors review all randomized phase III trials in first-line treatment with ICI for advanced or mRCC and selected prospective phase I-IV trials, that included patients with tumors with sarcomatoid features.
All these trials, in first-line treatment with ICI immunotherapy in combination with another ICI or TKI, included patients with mRCC with sarcomatoid features, corresponding from 5 to 15% of the study population. The efficacy and survival end points were superior in the sarcomatoid features subgroup with ICI in combination vs TKI in monotherapy, achieving overall response rates of 50–60%. A new benchmark has been established by trials reporting over 20 months in median overall survival. Even when considering ICI in monotherapy, the efficacy has been remarkable in patients with sarcomatoid features, demonstrating a striking consistency in these groundbreaking results. No biomarkers predictive of response to ICI were identified. The toxicity profile seems similar to the general study population.
Despite the limitations of the clinical trials design to infer definitive conclusions in the sarcomatoid features patients, the data overwhelmingly support that ICI-based therapy should be the preferred strategy.
Objective To study the methylation imprinting marks of two oppositely imprinted genes, H19 and MEST/PEG1 , in human testicular spermatozoa from azoospermic patients with different etiologies. ...Testicular spermatozoa are often used in intracytoplasmic sperm injection for treatment of male factor infertility, but the imprinting status of these cells is currently unknown. Design Experimental prospective study. Setting University research laboratory and private in vitro fertilization (IVF) clinic. Patient(s) A total of 24 men, five with anejaculation, five with secondary obstructive azoospermia, five with primary obstructive azoospermia, and nine with secretory azoospermia due to hypospermatogenesis. Intervention(s) Spermatozoa were isolated by micromanipulation from testicular biopsies. Main Outcome Measure(s) DNA methylation patterns were analyzed using bisulfite genomic sequencing with cloning analysis. Result(s) We found H19 complete methylation was statistically significantly reduced in secretory azoospermic patients with hypospermatogenesis, with one patient presenting complete unmethylation. Hypomethylation also affected the CTCF-binding site 6, involved in regulation of IGF2 expression. Regarding the MEST gene, all patients presented complete unmethylation although this was statistically significantly reduced in the anejaculation group. Conclusion(s) Testicular spermatozoa from men with abnormal spermatogenesis carry methylation defects in the H19 imprinted gene which also affect the CTCF-binding site, further supporting an association between the occurrence of imprinting errors and disruptive spermatogenesis.
Richter syndrome (RS) represents the clonal evolution of chronic lymphocytic leukemia with histological transformation into a high-grade B cell lymphoma (diffuse large B cell lymphoma - DLBCL) or ...Hodgkin lymphoma. Considering that RS is an uncommon condition with poor prognosis, few high-quality evidence is available. To overcome this unmet need, this meta-analysis aimed to pool efficacy of early clinical trials in Richter syndrome (DLBCL subtype).
MEDLINE, Scopus and Web of Science were searched up to May of 2023 to identify clinical trials decoying efficacy. The pooled complete response, objective response and intension-to-treat failure rates were calculated by pharmacological categories (classical chemotherapy, immunochemotherapy, immunotherapy, Bruton-tyrosine kinase inhibitors, targeted approaches, cell-based therapies and combinatorial regimens) using the Der-Simonian and Laird random-effects model. The Freeman-Tukey double arcsine method was used to estimate variance and confidence intervals. Heterogeneity was assessed using the I
method.
Overall, from 1242 studies identified, 30 were included, pooling data from 509 patients. The higher efficacy rates when, cell-based therapies were excluded, were achieved by immunochemotherapeutic regimens followed by combinatorial regimens, with complete response rates of 21.54% (IC95%14.93-28.87) and 23.77% (IC95% 8.70-42.19), respectively. Bispecific antibodies (alone or coupled with a chemotherapy debulking strategy) overtook Bruton tyrosine kinase inhibitors response rates. The latter, although achieving objective response rates above average, presented scarce complete response rates. Checkpoint inhibitors alone usually do not lead to complete responses, but their effectiveness may improve when combined with other agents, unveiling the importance of immune microenvironmental modulation.
This is the first meta-analysis of early clinical trials assessing the impact of different therapeutics in RS. By analyzing the pooled efficacy estimates, our work suggests the role of a tailor-made bridging therapy for young patients with RS eligible for allogeneic hematopoietic stem cell transplantation (alloSCT), formally the only curative strategy.
Carbon nanotubes (CNTs) are noteworthy, as they reinforce the metallic matrix, due to mechanical properties, such as the ~ 1.0 TPa Young module. To improve the maintenance of the commercially pure ...aluminum surface, multi-walled carbon nanotubes were incorporated into the aluminum surface with heat treatment by solid solubilization, in order to improve the surface properties of aluminum. The aluminum samples were chemically attacked for 30, 60 and 120 s and placed in a container with CNTs, being subjected to a temperature of 640 °C for 1 h. Then, the roughness was evaluated by a roughness meter for morphology in the scanning electron microscopy. An intensity of aggregation of CNTs was evaluated by XRD, and the Raman Spectra has evaluated the transfer of charge to the matrix. Microhardness was performed to evaluate the influence of the incorporation of CNTs in the matrix. The results obtained show that the incorporation of CNTs in the aluminum matrix increases the hardness in approximately 20% of the surface, in comparison with the control sample. The process of incorporating CNTs into the aluminum matrix by solubilization is a promising, simple and inexpensive alternative to improve the durability of the aluminum surface.
Graphic Abstract
Sertoli cells play a central role in spermatogenesis. They maintain the blood-testis barrier, an essential feature of seminiferous tubules which creates the proper environment for the occurrence of ...the spermatogenesis. However, this confinement renders germ cells almost exclusively dependent on Sertoli cells' nursing function and support. Throughout spermatogenesis, differentiating sperm cells become more specialized, and their biochemical machinery is insufficient to meet their metabolic demands. Although the needs are not the same at all differentiation stages, Sertoli cells are able to satisfy their needs. In order to maintain the seminiferous tubule energetic homeostasis, Sertoli cells react in response to several metabolic stimuli, through signaling cascades. The AMP-activated kinase, sensitive to the global energetic status; the hypoxia-inducible factors, sensitive to oxygen concentration; and the peroxisome proliferator-activated receptors, sensitive to fatty acid availability, are pathways already described in Sertoli cells. These cells' metabolism also reflects the whole-body metabolic dynamics. Metabolic diseases, including obesity and type II diabetes mellitus, induce changes that, both directly and indirectly, affect Sertoli cell function and, ultimately, (dys)function in male reproductive health. Insulin resistance, increased estrogen synthesis, vascular disease, and pubic fat accumulation are examples of metabolic-related conditions that affect male fertility potential. On the other hand, malnutrition can also induce negative effects on male sexual function. In this chapter, we review the molecular mechanisms associated with the nutritional state and male sexual (dys)function and the central role played by the Sertoli cells.
Worldwide there is serious concern about food and consumer safety
1
, namely with seafood products. Consequently, there is a major concern regarding food spoilage which make them unsuitable for ...human consumption. When deteriorating, seafood products suffers a complex series of events that begins when the organism die
1
,
2
. Therefore, there is a strong need for developing reliable seafood quality analysis. In the present study we surveyed histamine and spermidine in several seafood products (fresh fish and clams), purchased in a Portuguese traditional market.
Fresh seafood (Sardina pilchardus, Trachurus trachurus, Sparus aurata and Ruditapes decussata) were purchased in a market and taken to the laboratory in refrigerated containers. A total of 10 specimens were sampled from each species. Then samples were processed for analysis by homogenising in a phosphate buffer saline solution, centrifuged (10,000×g at 4 °C) for 15 min) and then stored at -80 °C until analysis. Seafood samples were assessed for the presence and content of histamine and spermidine using an indirect Enzyme Linked Immunosorbent assay (ELISA)
3
. The statistical analysis was performed using the Mann-Whitney U-test to determine differences between biogenic amine levels in seafood samples. Statistics was performed with a significance level of 5%, using the software Statistica 8.0 (Statsoft, Tulsa, OK, USA).
The results show variable results between species (from < LD to 184104 mg histamine/Kg wet weight). The highest levels were detected in T. trachurus samples and the lowest in clams. However, it was possible to detect the presence of the selected biogenic amines (histamine and spermidine) in most samples analysed. The lowest levels of spermidine were determined in R. decussata (1504.43 mg/kg w.w.), while the highest levels were determined in T. trachurus (184104 mg/Kg w.w.). Regarding histamine, the lowest levels were determined in R. decussata 20.23 mg/Kg w.w.) and the highest levels were measured in T. trachurus (460.25 mg/kg w.w.).
Although we are capable to detect the presence of the selected biogenic amines, in most of the samples the levels were below the limits established by Food and Drug Administration
4
and the European Union Commission Regulation (EC) No 1441/2007
5
.
Gastric cancer (GC) remains a public health problem, being the fifth most common cancer worldwide. In the western countries, the majority of patients present with advanced disease. Additionally, 65 ...to 75% of patients treated with curative intent will relapse and develop systemic disease. In metastatic disease, systemic treatment still represents the state of the art, with less than a year of median overall survival. The new molecular classification of GC was published in 2014, identifying four distinct major subtypes of gastric cancer, and has encouraged the investigation of new and more personalized treatment strategies. This paper will review the current evidence of immunotherapy in advanced gastric cancer.
Antibacterial resistance has become a challenging situation worldwide. The increasing emergence of multidrug-resistant pathogens stresses the need for developing alternative or complementary ...antimicrobial strategies, which has led the scientific community to study substances, formulas or active ingredients used before the antibiotic era. Honey has been traditionally used not only as a food, but also with therapeutic purposes, especially for the topical treatment of chronic-infected wounds. The intrinsic characteristics and the complex composition of honey, in which different substances with antimicrobial properties are included, make it an antimicrobial agent with multiple and different target sites in the fight against bacteria. This, together with the difficulty to develop honey-resistance, indicates that it could become an effective alternative in the treatment of antibiotic-resistant bacteria, against which honey has already shown to be effective. Despite all of these assets, honey possesses some limitations, and has to fulfill a number of requirements in order to be used for medical purposes.
Over the years, many biological and synthetic agents have been explored and tested in attempts to halt the spread of cancer and/or cure it. Currently, several natural compounds have and are being ...considered in this regard. For example, paclitaxel is a potent anticancer drug that originates from the tree
. Paclitaxel has several derivatives, namely, docetaxel and cabazitaxel. These agents work by disrupting microtubule assembling dynamics and inducing cell cycle arrest at the G2/M phase of the cell cycle, ultimately triggering apoptosis. Such features have helped to establish paclitaxel as an authoritative therapeutic compound against neoplastic disorders. After the completion of compound (hemi) synthesis, this drug received approval for the treatment of solid tumors either alone or in combination with other agents. In this review, we explore the mechanisms of action of paclitaxel and its derivatives, the different formulations available, as well as the molecular pathways of cancer resistance, potential risks, and other therapeutic applications. In addition, the role of paclitaxel in hematological malignancies is explored, and potential limitations in the therapeutic use of paclitaxel at the clinical level are examined. Furthermore, paclitaxel is known to cause increased antigen presentation. The immunomodulatory potential of taxanes, alone or in combination with other pharmacologic agents, is explored. Despite terpene-alkaloids derivatives' anti-mitotic potential, the impact of this class of drugs on other oncogenic pathways, such as epithelial-to-mesenchymal transition and the epigenetic modulation of the transcription profile of cancer cells, is also analyzed, shedding light on potential future chemotherapeutic approaches to cancer.
While in most patients the identification of genetic alterations causing dystrophinopathies is a relatively straightforward task, a significant number require genomic and transcriptomic approaches ...that go beyond a routine diagnostic set-up. In this work, we present a Becker Muscular Dystrophy patient with elevated creatinine kinase levels, progressive muscle weakness, mild intellectual disability and a muscle biopsy showing dystrophic features and irregular dystrophin labelling. Routine molecular techniques (Southern-blot analysis, multiplex PCR, MLPA and genomic DNA sequencing) failed to detect a defect in the
gene. Muscle
transcript analysis (RT-PCR and cDNA-MLPA) showed the absence of exons 75 to 79, seen to be present at the genomic level. These results prompted the application of low-coverage linked-read whole-genome sequencing (WGS), revealing a possible rearrangement involving
intron 74 and a region located upstream of the
gene. Breakpoint PCR and Sanger sequencing confirmed the presence of a ~8 Mb genomic inversion. Aberrant
transcripts were subsequently identified, some of which contained segments from the region upstream of
. Besides expanding the mutational spectrum of the disorder, this study reinforces the importance of transcript analysis in the diagnosis of dystrophinopathies and shows how WGS has a legitimate role in clinical laboratory genetics.
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