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OBJECTIVE: To treat the fetus presenting with in utero compromise due to a large vein of Galen malformation (VOGM) using glue embolization. METHODS: The fetus that was referred for termination of pregnancy at 30 weeks of gestation due to severe cardiomegaly, mild pericardial effusion and large VOGM was evaluated using ultrasound. There was reversed end diastolic flow in the umbilical artery Doppler indicating imminent fetal demise in the premature fetus weighing <1200 g. Considering the request of parents, a treatment similar to recently reported cases of VOGM embolization in utero was attempted as an emergency procedure to salvage the baby. Due to unavailability of coils, financial constraints and urgent need for intervention, n-butyl cyanoacrylate glue with lipiodol was used to embolize the venous outflow of VOGM outflow under ultrasonographic guidance. RESULTS: There was immediate correction of the umbilical artery Doppler waveform with the establishment of a normal flow pattern. The cardiomegaly resolved over 3 weeks and fetal MRI done 2 weeks later showed normal brain architecture with no evidence of hemorrhage or infarction. Pregnancy was continued for 4 weeks after the procedure and terminated at 36 weeks. A female baby weighing 1900 g was delivered by Cesarean section with an Apgar of 8/10. Though initially the baby did well, with mild ventriculomegaly reported on postnatal day 5, she eventually presented at 3 months of age with cardiac failure. As the MRI showed encephalomalacia, due to uncertainty of neurological outcome, further treatment was not pursued by the parents and the baby died a few days later. CONCLUSION: To our knowledge, this is the first report on the use of glue to treat VOGM prenatally. Though technically successful in correcting the in utero compromise, the baby eventually expired. Cases of in utero embolization using coils and glue have shown success in reversing prenatal pathology and improving survival. However, long-term outcomes including neurological status are yet to be reported.

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Targeted protein degradation (TPD) has emerged as a powerful approach for eliminating cancer-causing proteins through an "event-driven" pharmacological mode. Proteolysis-targeting chimeras (PROTACs), molecular glues (MGs), and hydrophobic tagging (HyTing) have evolved into three major classes of TPD technologies. Natural products (NPs) are a primary source of anticancer drugs and have played important roles in the development of TPD technology. NPs potentially expand the toolbox of TPD by providing a variety of E3 ligase ligands, protein of interest (POI) warheads, and hydrophobic tags (HyTs). As a promising direction in the TPD field, NP-based degraders have shown great potential for anticancer therapy. In this review, we summarize recent advances in the development of NP-based degraders (PROTACs, MGs and HyTing) with anticancer applications. Moreover, we put forward the challenges while presenting potential opportunities for the advancement of future targeted protein degraders derived from NPs.

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BACKGROUND: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. METHODS: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. RESULTS: We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. CONCLUSIONS: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

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INTRODUCTION: Bromodomain-containing protein 4 (BRD4), an important epigenetic reader, is closely associated with the pathogenesis and development of many diseases, including various cancers, inflammation, and infectious diseases. Targeting BRD4 inhibition or protein elimination with small molecules represents a promising therapeutic strategy, particularly for cancer therapy. AREAS COVERED: The recent advances of patented BRD4 degraders were summarized. The challenges, opportunities, and future directions for developing novel potent and selective BRD4 degraders are also discussed. The patents of BRD4 degraders were searched using the SciFinder and Cortellis Drug Discovery Intelligence database. EXPERT OPINION: BRD4 degraders exhibit superior efficacy and selectivity to BRD4 inhibitors, given their unique mechanism of protein degradation instead of protein inhibition. Excitingly, RNK05047 is now in phase I/II clinical trials, indicating that selective BRD4 protein degradation may offer a viable therapeutic strategy, particularly for cancer. Targeting BRD4 with small-molecule degraders provides a promising approach with the potential to overcome therapeutic resistance for treating various BRD4-associated diseases.

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Introduction: A hernia is an abnormal protrusion of the viscus through the normal or abnormal opening of its containing cavity. Lichtenstein tension-free mesh repair is a commonly performed surgery for hernia. Various studies have revealed atraumatic fixation of the mesh produces less pain without compromising the outcomes. Methods: This is a prospective analytical study conducted in a tertiary hospital over a year. Eighty patients with primary inguinal hernia undergoing open mesh repair were enrolled and divided into two groups with 40 patients in each group. Mesh fixation was done with N-butyl 2 cyano-acrylate glue in one group, while polypropylene 2-0 suture in the other group. Postoperative pain, the number of dosages of analgesia required, the incidence of hematoma/seroma formation, surgical site infection, and length of hospital stay were compared between the two groups. Data were analyzed using SPSS 25. Results: Visual analog scores were significantly reduced in the glue group at 12 h and 24 h (P<0.05) with a reduction of the mean number of analgesic doses from 6.42±0.984 in the suture group to 5.95±0.597 in the glue group (P<0.05). The operating time was significantly reduced from 70.03±4.376 minutes in the suture group to 58.43±4.540 min in the glue group (P<0.05), while there was no significant difference in the length of hospital stay. Five percent of cases in the suture group developed seroma while no SSI was reported in this study. Conclusions: This study demonstrates mesh fixation with cyanoacrylate glue in open hernioplasty for primary groin hernias is associated with reduced immediate postoperative pain, dose of analgesia required, and operating time in comparison to fixation with suture.

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Wound healing is a natural process that can be disrupted by disease. Nanotechnology is a promising platform for the development of new therapeutic agents to accelerate acute and chronic wound healing. Drug delivery by means of nanoparticles as well as wound dressings have emerged as suitable options to improving the healing process. The characteristics of mesoporous silica nanoparticles (MSNs) make them efficient carriers of pharmaceutical agents alone or in combination with dressings. In order to maximize the effect of a drug and minimize its adverse consequences, it may be possible to include targeted and intelligent release of the drug into the design of MSNs. Its use to facilitate closure of adjacent sides of a cut as a tissue adhesive, local wound healing, controlled drug release and induction of blood coagulation are possible applications of MSNs. This review summarizes research on MSN applications for wound healing. It includes a general overview, wound healing phases, MSN formulation, therapeutic possibilities of MSNs and MSN-based drug delivery systems for wound healing.

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PURPOSE: Dermoid excision combined with lamellar keratoplasty was one of the most common surgical techniques for corneal dermoid. Due to the huge shortage of corneal donors, small incision lenticule extraction (SMILE) derived lenticules might be the novel and feasible corneal grafts instead of traditional corneal donors. Therefore, we tried to use FG boned multi-layer lenticules as grafts in the treatment of corneal dermoid. METHODS: Five patients (the oldest patient was 54 years old and the youngest case was 5 years old) were diagnosed with corneal dermoid and complaining of blurred vision or unsatisfied cosmetic appearance. All patients underwent corneal dermoid excision combined with FG boned multi-layer corneal lenticules transplantation. Slit-lamp microscopy and anterior-segmental optical coherence tomography(AS-OCT)were used to observe ocular appearance, corneal grafts survival, epithelialization, transparency, interlamellar fluid accumulation and the degradation of FG. The preoperative and postoperative change of best-corrected visual acuity (BCVA) and astigmatism were respectively recorded. RESULTS: All patients were satisfied with the postoperative cosmetic results. BCVA had been increased and astigmatism had been decreased in all cases. We observed that the FG boned multi-layer corneal lenticules were covered with smooth corneal epithelium in one week after transplantation and successfully adhered to the corneal beds, without any dislocation or interlayer separation. FG was gradually degraded and absorbed within 1 month after surgery. The lenticule grafts grew well without rejection and kept transparency during the follow-up period. CONCLUSIONS: FG boned multi-layer lenticules would be the novel and feasible substitute for lamellar keratoplasty in the treatment of corneal dermoid. FG could not be only used as binder adhering multi-layer lenticules, closing the interlayer space of multi-layer lenticules, preventing the formation of interlayer fluid, but also increasing the thickness and toughness of lenticules, and therefore which is more facilitate to intraoperative suture.

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We present the case of a 40-year-old female who presented with abdominal pain, hematochezia, and melena for the past week and was diagnosed with a pseudoaneurysm emanating from the mid-splenic artery. The patient was managed with endovascular cyanoacrylate glue embolization, resulting in the complete resolution of an impending catastrophic hemorrhagic shock.

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Targeted therapies, such as small molecule kinase inhibitors, have made significant progress in the treatment of hematologic malignancies by directly modulating protein activity. However, issues such as drug toxicity, drug resistance due to target mutations, and the absence of key active sites limit the therapeutic efficacy of these drugs. Targeted protein degradation (TPD) presents an emergent and rapidly evolving therapeutic approach that selectively targets proteins of interest (POI) based on endogenous degradation processes. With an event-driven pharmacology of action, TPD achieves efficacy with catalytic amounts, avoiding drug-related toxicity. Furthermore, TPD has the unique mode of degrading the entire POI, such that resistance derived from mutations in the targeted protein has less impact on its degradation function. Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) are the most maturely developed TPD techniques. In this review, we focus on both preclinical experiments and clinical trials to provide a comprehensive summary of the safety and clinical effectiveness of PROTACs and MGDs in hematologic malignancies over the past two decades. In addition, we also delineate the challenges and opportunities associated with these burgeoning degradation techniques. TPD, as an approach to the precise degradation of specific proteins, provides an important impetus for its future application in the treatment of patients with hematologic malignancies.

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Background: Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase SLFN12 and the phosphodiesterase PDE3A. Formation of the complex activates SLFN12, which cleaves tRNALeu(TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumor cell lines from the cancer cell line encyclopedia, including glioblastoma cell lines. We therefore aim to characterize velcrins as novel therapeutic agents in glioblastoma. Materials and Methods: PDE3A and SLFN12 expression levels were measured in glioblastoma cell lines, the Cancer Genome Atlas (TCGA) tumor samples, and tumor neurospheres. Velcrin-treated cells were assayed for viability, induction of apoptosis, cell cycle phases, and global changes in translation. Transcriptional profiling of the cells was obtained. Xenograft-harboring mice treated with velcrins were also monitored for survival. Results: We identified several velcrin-sensitive glioblastoma cell lines and 4 velcrin-sensitive glioblastoma patient-derived models. We determined that BAY 2666605 crosses the blood-brain barrier and elicits full tumor regression in an orthotopic xenograft model of GB1 cells. We also determined that the velcrins BAY 2666605 and BRD3800 induce tumor regression in subcutaneous glioblastoma PDX models. Conclusions: Velcrins have antitumor activity in preclinical models of glioblastoma, warranting further investigation as potential therapeutic agents.

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Over the past two decades, molecular glues (MGs) have gradually attracted the attention of the pharmaceutical community with the advent of MG degraders such as IMiDs and indisulam. Such molecules degrade the target protein by promoting the interaction between the target protein and E3 ligase. In addition, as a chemical inducer, MGs promote the dimerization of homologous proteins and heterologous proteins to form ternary complexes, which have great prospects in regulating biological activities. This review focuses on the application of MGs in the field of drug development including protein-protein interaction (PPI) stability and protein degradation. We thoroughly analyze the structure of various MGs and the interactions between MGs and various biologically active molecules, thus providing new perspectives for the development of PPI stabilizers and new degraders.

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Purpose: To describe the use of an amniotic membrane graft (AMG) with fibrin sealant to address an overfiltering trabeculectomy flap encountered intraoperatively. Observations: A 35-year-old female with severe primary open angle glaucoma underwent trabeculectomy with mitomycin C due to uncontrolled intraocular pressure (IOP). Intraoperatively, the elastic nature of the scleral flap led to overfiltration, causing persistent anterior chamber shallowing despite numerous sutures. To decrease but not completely shut down aqueous outflow through the trabeculectomy flap, we utilized AMG and fibrin sealant to stabilize the flap. Postoperatively, the patient had a formed anterior chamber, elevated bleb and significantly reduced IOP, without the need for additional glaucoma medications. Conclusions and importance: Amniotic membrane grafts (AMG) with fibrin sealant may help regulate aqueous flow efflux, maintain anterior chamber stability, and mitigate the risk of postoperative hypotony in trabeculectomy surgery. AMG was chosen in this setting given its anti-inflammatory, anti-fibrotic properties, as well as its optically clear nature to allow for post-operative visualization of the flap. AMG allows for early postoperative stabilization of the scleral flap without complete obstruction, and may be useful in patients at risk of early postoperative hypotony.

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Introduction: The popular wound closure methods for carpal tunnel decompression (CTD) include non-absorbable and absorbable sutures which have comparable results in clinical outcomes. However, these wound closure methods are recommended to keep a wound dry which may limit some ADLs. We conducted a prospective randomized controlled trial that compares clinical outcomes and cost-effectiveness in a skin closure following CTD between absorbable sutures plus a 2-octyl cyanoacrylate tissue adhesive (2OCA) versus non-absorbable skin sutures plus a waterproof dressing (NSPWD). Materials and Methods: We enrolled 120 patients undergoing CTD into two groups: 2OCA and NSPWD, with 60 patients in each group. Number of dressing changes, Quick DASH, pain VAS, cosmetic VAS, patient satisfaction VAS, and Hollander wound evaluation score, cost-effectiveness, and post-operative complications were collected at pre-operative period and two and six weeks post-operatively. Results: Slightly better patient satisfaction VAS (7.9 vs 7.2, p=0.018) and cosmetic VAS (8.0 vs 7.2, p=0.025) were observed in 2OCA at 2 weeks. Meanwhile, NSPWD revealed lesser times of dressing change (Median, mode, IQR: 0/0/0 vs 2/3/2, p<0.001). The total wound-related costs include dressing change and suture removal cost ($15.9 for 2OCA vs $19.2 for NSPWD, p=0.002) although an initial wound-related cost in 2OCA was higher ($15.7/case vs $7.9/case, p<0.001). Conclusion: Our study revealed that the supplementary tissue adhesive to absorbable sutures following CTD could reduce total wound-related costs while clinical outcomes might not be considered clinically significant.

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BACKGROUND: Propolis was added to the European baseline series (EBS) in 2019. OBJECTIVES: To investigate the frequency and relevance of positive patch tests to propolis in the EBS and to study co-reactivities. PATIENTS AND METHODS: Retrospective study in patients patch tested between June 2019 and November 2023 in a university hospital in Amsterdam, The Netherlands. RESULTS: Of 3134 consecutive patients, 299 (9.5%) had a positive reaction to propolis 10% pet. Only nine reactions (3%) were judged to be clinically relevant. There were significant co-reactivities to Myroxylon pereirae resin (balsam of Peru), colophonium, fragrance mixes 1 and 2, and to limonene and linalool hydroperoxides. A steep increase in rates of positive reactions to propolis was observed from 2020 to 2023. This was highly likely the result of the replacement of Chinese propolis with Brazilian propolis by the manufacturer. CONCLUSIONS: Positive patch tests for propolis are very frequent in Amsterdam, but only a few of these reactions are relevant. Most are probably (pseudo-)cross-reactions in patients with fragrance allergies. Propolis in the EBS has very limited value for dermatologists and patients in The Netherlands. Changes in patch test materials should be provided to all users to avoid misinterpretation of patch test results.

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The sticky trap is probably the most cost-effective tool for catching insect pests, but the identification and counting of insects on sticky traps is very labour-intensive. When investigating the automatic identification and counting of pests on sticky traps using computer vision and machine learning, two aspects can strongly influence the performance of the model - the colour of the sticky trap and the device used to capture the images of the pests on the sticky trap. As far as we know, there are no available image datasets to study these two aspects in computer vision and deep learning algorithms. Therefore, this paper presents a new dataset consisting of images of two pests commonly found in post-harvest crops - the red flour beetle (Tribolium castaneum) and the rice weevil (Sitophilus oryzae) - captured with three different devices (DSLR, webcam and smartphone) on blue, yellow, white and transparent sticky traps. The images were sorted by device, colour and species and divided into training, validation and test parts for the development of the deep learning model.

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Rice straw is considered an agricultural waste harmful to the environment, which is abundant in most parts of the world. From this point, the present study is devoted to preparing new composites of two types of glue based on rice straw as a plentiful, low-cost matrix. Straw glue samples were prepared by mixing 20% wt. of rice straw with 80% wt. of animal glue (RS-An) and polyvinyl acetate (RS-PVAC) at different thicknesses of 1, 2, and 3 cm. The chemical composition of the prepared samples was identified by energy dispersive X-ray analysis and their morphology was examined using a scanning electron microscope. The mechanical test explored that RS-An and RS-PVAC respectively required a stress of 25.2 and 25.5 MPa before reaching the breaking point. γ-ray shielding performance was analyzed and determined at numerous photon energies from 0.059 to 1.408 MeV emitted from five-point γ-rays sources using NaI (Tl). Linear attenuation coefficient was calculated by obtaining the area under the peak of the energy spectrum observed from Genie 2000 software in the presence and absence of the sample. The experimental results of mass attenuation coefficient were compared with theoretical data of XCOM software with relative deviation ranging from 0.10 to 2.99%. Geant4 Monte Carlo simulation code was also employed to validate the experimental results. The relative deviation of XCOM and Geant4 outcomes was 0.09-1.77%, which indicates a good agreement between them. Other radiation shielding parameters such as half value layer (HVL), tenth value layer, and mean free path were calculated in three ways: experimentally, theoretically from the XCOM database, and by simulation using Geant4 code. Additionally, effective atomic number (Zeff), effective atomic number (Neff), equivalent atomic number (Zeq), and buildup factors were evaluated. It was confirmed that the γ-ray shielding properties were further boosted by mixing rice straw with the animal glue compared to the synthetic one.

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Background: Our review of 12 articles for this perspective showed the frequency of intraoperative thoracic and/or lumbar CSF fistulas/dural tears (DT) ranged from 2.6% - 8% for primary surgical procedures. Delayed postoperative CSF leak/DT were also diagnosed in 0.83% (17/2052 patients) to 14.3% (2/14 patients) of patients undergoing thoracic and/or lumbar procedures. Further, the rate of recurrent postoperative CSF leaks/DT varied from 13.3% (2/15 patients) to 33.3% (4/12 patients). Methods: Intraoperative, postoperative delayed, and recurrent postoperative traumatic postsurgical thorac CSF leaks/DT can be limited by performing initially sufficient operative decompressions and/or decompressions/fusions (i.e., utilizing adequate open exposures vs. inadequate minimally invasive (MI) approaches). The incidence of CSF leaks/DT can be further reduced by spine surgeons' utilization of operating microscopes, and their avoiding routine attempts at total synovial cyst excision and/or complete resection of hypertrophied/ossified yellow ligament in the presence of significant dural adhesions. Results: Multiple CSF leak/CT repair techniques included; using interrupted, non-resorbable sutures for direct dural repairs (i.e. 7-0 Gore-Tex sutures where the suture is larger than the needle thus plugging needle holes), and adding where needed muscle patch grafts, microfibrillar collagen, the rotation of Multifidus muscle pedicle flaps, fibrin sealants (FS)/fibrin glues (FG), lumbar drains (LD), and/or lumbo-peritoneal (LP) shunts. Conclusion: Intraoperative, postopertive delayed, and/or recurrent postoperative thorac and/or lumbar traumatic surgical CSF leaks can be reduced by choosing to initially perform the appropriately extensive open operative decompressions and/or decompresssions/fusions. It is critical to use an operating microscope, non-resorbable interrupted sutures, and where necessary, muscle patch grafts, microfibrillar collagen, the rotation of Multifidus Muscle Pedicle Flaps, FS/FG, LD, and/or LP shunts.

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Background: Type II endoleaks are common and embolization is often performed if treatment is necessary. Although transarterial embolization is common, other methods including trans-caval embolization are also utilized. Complications can occur and we report a case of infection that was challenging to diagnose and treat. There is no data regarding the risk of aortic stent graft infection after trans-caval embolization with n-butyl 2-cyanoacrylate (n-BCA) glue of a type II endoleak. Case Description: We report a rare case of infected, Gore Excluder infrarenal stent graft after transcaval embolization with coil and n-BCA glue to treat a type II endoleak in a 71-year-old male. The endoleak caused a rapid sac enlargement. The stent graft was placed 5 years earlier electively. Soon after the endoleak embolization, the patient experienced abdominal pain and malaise. There was an intense inflammatory reaction involving the aneurysm wall and the adjacent bowel mesentery. Our differential included normal inflammation after embolization vs. infection and this was difficult to distinguish. The infection was confirmed by positron emission tomography scan and tissue biopsy. The patient was deemed high-risk for surgery because of his extensive cardiac history, status post coronary bypass and tissue mitral valve replacement, congestive heart failure with residual left ventricular ejection fraction of 36%. He was optimized by correcting fluid status, administration of intravenous antibiotic, and nutrition consultation with dietary supplementation before surgery over the course of 2 weeks. The graft was explanted through a transabdominal approach, and the aorta was reconstructed with cryopreserved allograft. Interestingly, the small and large intestine with their mesentery were found to be plastered to the aneurysm sac. The post-operative course was unremarkable except for a transient acute kidney injury that resolved within 1 week. Follow-up computed tomography scan at 6 months showed widely patent bypass. Conclusions: Glue embolization induces inflammation promoting thrombus formation inside the aneurysm sac. With a transcaval approach to the sac, there is the risk of extravasation of glue outside the sac as well as contamination of the graft with instrumentation. Differentiating between inflammation and infection can be difficult, and tissue biopsy provided the most conclusive diagnosis. Risk minimization considerations include, pre-operative optimization, a transabdominal approach, ureteral stenting, and tissue buttressing of anastomosis.