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KRAS inhibitors have demonstrated exciting preclinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on the tumor microenvironment using a library of KrasG12D, p53-mutant, murine pancreatic ductal adenocarcinoma-derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term tumor efficacy. Our findings show that SOS1 and MEK inhibitors (SOS1i+MEKi) suppressed tumor growth in syngeneic models and increased intratumoral CD8+ T cells without durable responses. Single-cell RNA sequencing revealed an increase in inflammatory cancer-associated fibroblasts (iCAF), M2 macrophages, and a decreased dendritic cell (DC) quality that ultimately resulted in a highly immunosuppressive microenvironment driven by IL6+ iCAFs. Agonist CD40 treatment was effective to revert macrophage polarization and overcome the lack of mature antigen-presenting DCs after SOS1i+MEKi therapy. Treatment increased the overall survival of KPCY tumor-bearing mice. The addition of checkpoint blockade to SOS1i+MEKi combination resulted in tumor-free mice with established immune memory. Our data suggest that KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong antitumor effects. SIGNIFICANCE: Combination of SOS1 and MEK inhibitors increase T cell infiltration while blunting pro-immune myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong anti-tumor effects.
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Carcinoma Ductal Pancreático , Inmunoterapia , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Proteína SOS1 , Microambiente Tumoral , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Ratones , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Proteína SOS1/genética , Proteína SOS1/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Inmunoterapia/métodos , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ratones Endogámicos C57BL , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , FemeninoRESUMEN
Migraine, a common affliction, manifests as debilitating headaches often accompanied by auras. However, hemiplegic migraine presents an unusual symptomatology, inducing unilateral paralysis during attacks. This condition, occurring in two forms, familial and sporadic, merits attention due to its rarity. To raise awareness of this ailment, we recount the case of a 33-year-old woman. This instance serves as a poignant reminder of the potential severity and complexity of hemiplegic migraines. By shedding light on this less-understood variant, we aim to enhance recognition and understanding within medical communities and among the general public. Additionally, emphasizing the importance of thorough history taking in identifying characteristic features, such as the presence of auras or unilateral paralysis preceding headaches, is paramount. Understanding these nuances aids in accurate diagnosis and formulation of tailored management strategies. It's imperative to recognize the distinct characteristics of hemiplegic migraines to ensure timely and appropriate management for affected individuals, offering them relief and improving their quality of life.
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Videos are considered as most trustworthy means of communication in the present digital era. The advancement in multimedia technology has made video content sharing and manipulation very easy. Hence, the video authenticity is a challenging task for the research community. Video forensics refer to uncovering the forgery traces. The detection of spatiotemporal object-removal forgery in surveillance videos is crucial for judicial forensics, as the presence of objects in the video has significant information as legal evidence. The author proposes a passive max-median averaging motion residual algorithm for revealing the forgery traces, successfully giving visible object-removal traces followed by a deep learning approach, YOLO-V8, for forged region localization. YOLO-V8 is the latest deep learning model, which has a wide scope for real-time application. The proposed method utilizes YOLO-V8 for object-removal forgery in surveillance videos. The network is trained on the SYSU-OBJFORG dataset for object-removal forged region localization in videos. The fine-tuned YOLO-V8 successfully classifies and localizes the object-removal tampered region with an F1-score of 0.99 and a precision of 0.99. The observed high confidence score of the bounding box around the forged region makes the model reliable. This fine-tuned YOLO-V8 would be a better choice in real-time applications as it solves the complex object-based forgery detection in videos. The performance of the proposed system is far better than the existing deep learning approach.
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Acquired hallux varus deformity secondary to postburn contracture is a rare condition. It causes cosmetic disfigurement, pain, and inability to wear a shoe. Soft-tissue procedures and tendon transfers have been described for correction; however, these may require multiple operations and the outcome may be poor. We report a 6-year-old neglected case of hallux varus deformity secondary to burn contracture successfully managed by contracture release with pivotless distraction technique using a biplanar distractor and skin grafting with Z-plasty in the same procedure. The deformity was corrected to a lesser extent and with good functional outcomes. The scar was excised and Z-plasty was performed. The medial joint capsule was released. We used gradual differential distraction with monitoring on sequential radiographs. Pain-free flexion of 45° and extension of 40° were achieved and the patient was able to wear shoes after 4 weeks postoperatively. Hallux varus is a multidimensional deformity. A severe and rigid deformity might not respond well to tendon transfers in a single stage. Our described technique can be used to correct rigid hallux varus deformity with preservation of joint function.
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Quemaduras , Contractura , Hallux Valgus , Hallux Varus , Hallux , Niño , Humanos , Quemaduras/complicaciones , Contractura/diagnóstico por imagen , Contractura/etiología , Contractura/cirugía , Hallux/cirugía , Hallux Valgus/complicaciones , Hallux Varus/diagnóstico por imagen , Hallux Varus/etiología , Hallux Varus/cirugía , Transferencia Tendinosa/métodosRESUMEN
Objectives: The reconstruction of large bony defect caused by tumor resection can be managed by different technique like bone graft, Masquelet technique, mega-prosthesis etc. Literature lacks studies discussing Masquelet technique in tumor cases especially pertaining to infected tumor in adults. We aimed to determine 1) How often and how fast is the bone healing achieved after resection greater than 10 cm bone in tumour patient's using Masquelet technique?, 2) Whether Masquelet technique can achieve optimum outcomes in adult infected cases too? Methods: We reviewed 154 patients of benign & malignant tumour managed by us between 2013 and 2019. Patients belonging to all the age group with infected tumor/diaphysial tumor/periarticular tumor, where single stage surgery or mega-prosthesis is not a viable option and were treated with Masquelet technique for reconstructing a bone defect of at least 10 cm were included in our study. We evaluated outcomes of eight patients for four parameters i.e. bony union, healing index, number of re-do surgeries required and limb length discrepancy. Results: Mean age of our study group was 20.25 years and patients followed for mean duration of 3.36 years. Mean bone loss after tumor resection was 13.1 cm (range = 11.5 cm to 15 cm). There was no sign of recurrence of tumor in any patient at the time of last follow up. Average time required to achieve bony union was 23.25 months (mean healing index of 1.67 months/cm). All but one patient achieved bony union. Mean limb length discrepancy seen was 1.44cm. Infected cases showed low healing index with higher percentage of re-do surgeries. Conclusion: Induced membrane technique is quick, safe and reliable alternative method of reconstruction to mega-prosthesis in cases with all age group where risk of failure of mega-prosthesis is high, either due to infection or shorter expected lifespan of prosthesis. However, obtaining union can be a difficult preposition in infected tumor cases and multiple surgeries may be required to get the desired result even after two stages. However, a comparative study with large sample size is required to further validate our results.
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BACKGROUND: Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy. METHODS: We designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor. RESULTS: IM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3, a transcription factor required for DC development. CONCLUSIONS: By simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.
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Neoplasias , Receptor Toll-Like 9 , Humanos , Ratones , Animales , Receptor Toll-Like 9/metabolismo , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Oligonucleótidos Antisentido , Células DendríticasRESUMEN
Disseminated gonorrheal infections with cardiac involvement are rare, with fewer than 100 cases reported. The increasing prevalence of gonococcal infections and increasing antibiotic resistance represent a concerning challenge to public health. Here we report a case of antibiotic-resistant gonococcal endocarditis presenting with cardiogenic shock and discuss principles of diagnosis and treatment.
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Background: Conventional methods of pedicle-screw placement have higher breach rates due to variations in pedicle trajectories. Objective: We studied the accuracy of patient-specific, three-dimensional (3D)-printed laminofacetal-based trajectory guide for pedicle-screw placement in the subaxial-cervical and thoracic spine. Materials and Methods: We enrolled 23 consecutive patients who underwent subaxial cervical and thoracic pedicle-screw instrumentation. They were divided into two groups: group A (cases without spinal deformity) and group B (cases with pre-existing spinal deformity). Patient-specific, 3D-printed laminofacetal-based trajectory guide for each instrumented level was designed. The accuracy of screw placement was assessed on postoperative computed tomography (CT) using the Gertzbein-Robbins grading. Results: A total of 194 pedicle screws (114 cervical and 80 thoracics) were placed using trajectory guides, of which 102 belonged to group B (34 cervical and 68 thoracics). Out of a total of 194 pedicle screws, 193 had clinically acceptable placement (grade A: 187; grade B: 6; and grade C: 1). In the cervical spine, 110 pedicle screws out of a total of 114 had grade A placement (grade B: 4). In the thoracic spine, 77 pedicle screws out of a total of 80 had grade A placement (grade B: 2; grade C: 1). Out of a total of 92 pedicle screws in group A, 90 had grade A placement, and the rest 2 had grade B breach. Similarly, 97 out of a total of 102 pedicle screws in group B were placed accurately, 4 had grade B and another had a grade C breach. Conclusions: Patient-specific, 3D-printed laminofacetal-based trajectory guide may help in accurate placement of subaxial cervical and thoracic pedicle screws. It may help reduce surgical time, blood loss, and radiation exposure.
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Tornillos Pediculares , Fusión Vertebral , Humanos , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/cirugía , Cuello , Fusión Vertebral/métodos , Impresión TridimensionalRESUMEN
CASES: Concomitant ipsilateral intracapsular and extracapsular fractures of the femoral neck, also termed "segmental fracture neck femur," are rare injuries, especially in physiologically young patients. We present 3 such cases that successfully underwent operative fixation with an extramedullary implant. CONCLUSION: Good clinical outcomes may be obtained after osteosynthesis with extramedullary fixation devices in concomitant ipsilateral intracapsular and extracapsular fractures of the femoral neck in young patients (<60 years). They should be followed for a long duration to look for avascular necrosis.
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Fracturas del Cuello Femoral , Fracturas de Cadera , Osteonecrosis , Humanos , Fracturas de Cadera/cirugía , Fracturas del Cuello Femoral/diagnóstico por imagen , Fracturas del Cuello Femoral/cirugía , Cuello Femoral/cirugía , Fijación Interna de FracturasRESUMEN
Background: Various operative procedures have been described for the treatment of traumatic paraplegia caused by unstable thoracolumbar fractures. We prospectively evaluated interbody fusion (IBF) with SS-PSF in these cases with regard to clinico-radiological outcome with the objectives: (1) Does IBF and short segment pedicle screw fixation (SS-PSF) prevent progression of kyphotic angle after surgery? (2) Can this procedure be safely performed in the setting of acute trauma?. Methods: Sixteen patients suffering from traumatic paraplegia caused by acute unstable thoracolumbar fractures were enrolled prospectively and underwent IBF with SS-PSF. They were evaluated for magnitude of shortening in spine, progression of kyphotic angle, and neurological improvement by American spinal injury association scale (ASIA). Results: Out of total sixteen, 14 patients were ASIA grade A and 2 were grade C, at the time of presentation. Thirteen out of these 14 remained grade A and one improved to B. Both the patients who had grade C involvement at the time of presentation improved to grade D at one-year follow-up. The mean blood loss was 750 ml (range; 650 ml-1150 ml). Mean kyphotic angle decreased from 20.6° (range; 13° to 37°) preoperatively to 6.2° (range; 3° to 10°) at postoperative day 2 (p = 0.002). Its mean value after 6 months was 6.5° (range; 3° to 11°). The procedure resulted in mean spinal column shortening of 18 mm (range; 16 mm-22 mm) in the spinal column. All the patients achieved bony union by a mean duration of 3.9 months (range; 3 months-6 months). Conclusions: IBF with SS-PSF has the shortest possible instrumented construct for thoracolumbar junction fusion done by posterior approach. The interbody fusion for unstable thoracolumbar junction fractures prevents the progression of kyphotic angle post-operatively. Level of evidence: Level 4.
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BACKGROUND: There are various classification systems described in the literature for managing bone defects in revision knee arthroplasty (RTKA). We analysed the reliability and usefulness of these classification systems. QUESTIONS/PURPOSES: (1) To review and critique the various classification systems proposed for bone loss in RTKA. (2) Among all the proposed classifications which one is the most commonly used by surgeons to report their results. (3) What is the reliability of various bone defect classification systems for RTKA. In this review, we have assessed the studies validating those classifications with a detailed description of the limitations and the proposed modifications. METHODS: This systematic review was conducted following PRISMA guidelines. Pubmed/Medline, CINAHL, EMBASE, Scopus, Cochrane databases and Web of Science databases were searched using multiple search terms and MeSH terms where possible. Studies meeting inclusion criteria were assessed for statistical parameters of reliability of a classification system. RESULTS: We found 16 classification systems for bone defects in RTKA. Six studies were found evaluating a classification system with reporting their reliability parameters. Fifty-four studies were found which classified bone loss using AORI classification in their series. AORI classification is most commonly reported for classifying bone defects. Type T2B and F2B are the most common bone defects in RTKA. The average kappa value for AORI classification for femoral bone loss was 0.38 (0.27-0.50) and 0.76 (0.63-1) for tibial bone loss assessment. CONCLUSION: None of the available classification systems is reliably established in determining the bone loss and treatment plans in RTKA. Among all, AORI classification is the most widely used system in clinical practice. The reliability of AORI Classification is fair for femoral bone loss and substantial for tibial bone loss.
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Artroplastia de Reemplazo de Rodilla , Prótesis de la Rodilla , Humanos , Artroplastia de Reemplazo de Rodilla/métodos , Reproducibilidad de los Resultados , Reoperación , Tibia/cirugía , Articulación de la Rodilla/cirugíaRESUMEN
Background: Genu valgum is a common disorder affecting adolescents and young adults. Treatment of this disorder requires restoration of normal mechanical axis alignment and joint orientation, for which it is important to assess whether the deformity arises from the distal femur, knee joint, or proximal tibia. Most commonly, the deformity originates from the distal femur, and various osteotomies of the distal femur have been described1-6. The presently described wedgeless V-shaped osteotomy7,8 is a good option among the various alternative procedures listed below. Description: The anesthetized patient is placed in the supine position on a radiolucent operating table. A bolster is placed beneath the knee to relax the posterior structures. A medial longitudinal skin incision is made that extends from the level of the medial joint line to 5 cm proximal to the adductor tubercle. The vastus medialis is identified and elevated anteriorly by detaching it from its distal and posterior aspects. The leash of vessels underneath the vastus medialis is identified, and the apex of the V-shaped osteotomy is kept just proximal to it. The anterior arm of the V is kept longer than the posterior one, both of them are kept perpendicular to each other, and the apex of the V is made to point distally. The osteotomy is performed on the medial cortex with use of an oscillating saw or multiple drill holes that are then connected using a thin osteotome. Care is taken not to utilize a saw or drill on the lateral cortex. A gentle valgus thrust is applied to break the lateral cortex without periosteal disruption. The apex of the V osteotomy on the proximal fragment is trimmed, and the deformity is corrected with varus force. The osteotomy site is stabilized with use of an anatomically contoured distal medial femoral locking plate or a medial proximal tibial L-shaped buttress plate (of the contralateral side). The implant position is verified under a C-arm image intensifier. The wound is closed in layers over a suction drain in a standard manner. Alternatives: Various types of corrective osteotomies of the distal femur have been described in the literature, including the lateral opening wedge, medial closing wedge, dome, and spike osteotomies1-6. All of these procedures have certain limitations and shortcomings. Rationale: The wedgeless V-shaped osteotomy is another described procedure that is inherently stable7,8. It is a safe procedure and yields good clinical outcomes8,9. The posterior arm of the V-shaped osteotomy is kept smaller than the anterior arm. The proximal cortical bone is allowed to dig into the cancellous bone of the wider distal metaphysis during deformity correction. Trimming the apex of proximal bone end after making the osteotomy facilitates the process. Expected Outcomes: In a study of 46 patients with a mean age of 16.9 years (range, 15 years to 23 years), Gupta et al.8 reported that the mean radiographic tibiofemoral angle improved from 22.2° (range, 16° to 29°) preoperatively to 5.1° (range, 0° to 10°) postoperatively (p < 0.001). Similarly, the mean lateral distal femoral angle improved from 79.2° preoperatively to 89.1° postoperatively (p < 0.001) and the mean mechanical axis deviation improved from 19.6 mm preoperatively to 3.7 mm postoperatively (p < 0.001). A total of 44 of 46 cases had an excellent functional outcome, with the other 2 having good outcomes. None of the patients in the study had an unsatisfactory outcome. Important Tips: It is important to keep the whole lower limb accessible to the image intensifier intraoperatively.Identification of the leash of vessels underneath the vastus medialis is important to decide the level of the osteotomy.It is important to preserve the periosteal sleeve on the lateral aspect of the femur. Acronyms and Abbreviations: CORA = center of rotation of angulationECG = electrocardiogramLDFA = lateral distal femoral angleMAD = mechanical axis deviationMPTA = medial proximal tibial angle.
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Immune checkpoint blockade (ICB) has substantially improved the prognosis of patients with cancer, but the majority experiences limited benefit, supporting the need for new therapeutic approaches. Up-regulation of sialic acid-containing glycans, termed hypersialylation, is a common feature of cancer-associated glycosylation, driving disease progression and immune escape through the engagement of Siglec receptors on tumor-infiltrating immune cells. Here, we show that tumor sialylation correlates with distinct immune states and reduced survival in human cancers. The targeted removal of Siglec ligands in the tumor microenvironment, using an antibody-sialidase conjugate, enhanced antitumor immunity and halted tumor progression in several murine models. Using single-cell RNA sequencing, we revealed that desialylation repolarized tumor-associated macrophages (TAMs). We also identified Siglec-E as the main receptor for hypersialylation on TAMs. Last, we found that genetic and therapeutic desialylation, as well as loss of Siglec-E, enhanced the efficacy of ICB. Thus, therapeutic desialylation represents an immunotherapeutic approach to reshape macrophage phenotypes and augment the adaptive antitumor immune response.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Ratones , Animales , Glicosilación , Macrófagos Asociados a Tumores , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/genética , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Microambiente TumoralRESUMEN
Background: Many quantitative MRI parameters and clinical scores have been used patients with lumbar spinal stenosis (LSS). However, the correlation between clinical scores and MRI parameters is not very clear. The objective of the study was to find out the correlation between commonly used clinical scoring systems and quantitative MRI parameters. Methods: Eighty two patients (more than 40 years) with clinical and radiological characteristics of degenerative LSS completed 10 clinical questionnaires which included Oswestry disability index (ODI), Swiss spinal stenosis (SSS) questionnaire, Quebec pain disability scale (QPD), Visual analogue scale (VAS), modified Japanese orthopaedic association scale (mJOA), Pain disability index (PDI), Short form health survey (SF-36), Self-paced walking test (SPWT), Euro quality of life-5D (EQ-5D) and Neurogenic claudication outcome score (NCOS). Lumbosacral MRIs were performed and 8 quantitative parameters namely transverse & AP diameter of dural sac (TDD, APDD), anteroposterior diameter of spinal canal (APDS), ligamentous interfacet distance (LID), mid-sagittal diameter of thecal sac (MSDT), cross-sectional area dural sac (CSAD), lateral recess depth and angle (LRD, LRA) were measured at the maximum stenotic level at the level of the disc. The clinical and radiological parameters were then statistically analysed. Results: There were 51 females and 31 males in the study with a mean age of 53.0253.02 ± 9.18 years. NCOS score had a moderate correlation with CSAD, LID and TDS (p<0.05,0.7>r ≥ 0.3). MSDT showed a moderate negative correlation with SSS, VAS, ODI and QPD (p<0.05,0.7>r ≥ 0.3). LRD had a moderate negative correlation with ODI and VAS score (p<0.05,0.7>r ≥ 0.3). LRA had a moderate correlation with the EQ-5D and ODI (p<0.05,0.7>r ≥ 0.3). The CSAD had a moderate negative correlation with PDI (r = -0.383, p = 0.000). For all other comparisons, there was poor or no correlation. MRI parameters showed poor or no correlation with most of components of SF-36 score. Conclusions: A poor correlation or no correlation was noted for most of the MRI parameters when compared to commonly used clinical scores. Hence, poor MRI's don't necessarily mean poor clinical scores in LSS. The role of MRI parameters should be supplementary and overreliance on them in LSS management should be avoided.
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T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)-interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5-IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5-IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a+ NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5-IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ-inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a+ CXCR6+ NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance.
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Integrina alfa1 , Neoplasias , Animales , Células Dendríticas , Inmunoterapia , Integrina alfa1/metabolismo , Interleucina-12/metabolismo , Células Asesinas Naturales , Ratones , Neoplasias/patología , Receptor de Muerte Celular Programada 1/metabolismo , Microambiente TumoralRESUMEN
Monoacylglycerol is a metabolic key serine hydrolase engaged in the regulation of the signalling network system of endocannabinoids, which is associated with various physiological processes like pain, inflammation, feeding cognition, and neurodegenerative diseases like Alzheimer's and Parkinson's disease. The monoacylglycerol was also found to act as a regulator and the free fatty acid provider in the proliferation of cancer cells as well as numerous aggressive tumours such as colorectal cancer, neuroblastoma, and nasopharyngeal carcinoma. It also played an important role in increasing the concentration of specific lipids derived from free fatty acids like phosphatidic acid, lysophosphatidic acid, sphingosine-1-phosphate, and prostaglandin E2. These signalling lipids are associated with cell proliferation, survival, tumour cell migration, contribution to tumour development, maturation, and metastases. In this study, we present a review on structurally diverse MAGL inhibitors, their development, and their evaluation for different pharmacological activities.
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Inhibidores Enzimáticos , Monoacilglicerol Lipasas , Neoplasias , Endocannabinoides/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/metabolismo , Monoglicéridos/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
Background: We sought to determine the current level of exposure to and interest in off-pump coronary artery bypass and beating heart surgery techniques regarding cardiothoracic surgical residents in the United States. Methods: An email survey consisting of 6 questions was sent to all cardiothoracic surgery residents of approved cardiothoracic training programs in the United States. The survey was emailed using the Qualtrics XM cloud-based survey platform. When the email responses were received, the answers to the survey questions were tabulated by the Qualtrics software and the resident's institution and year of graduation from their residency was noted. Results: Of 400 surveys sent, we received 99 responses for a response rate of 25%. A total of 78% of cardiothoracic surgery residents reported that they are at programs that do off-pump coronary artery bypass or beating heart surgery infrequently, noting that these cases are done in less than 5% of the coronary artery bypass graftings to which they are exposed. A total of 51% responded that they do not feel comfortable with off-pump coronary artery bypass grafting under any circumstances. A total of 49% reported some comfort with the technique with most of these respondents noting that they would do off-pump coronary artery bypass or beating heart surgery on a selective basis if the clinical situation arose and 4% plan to do off-pump coronary artery bypass routinely. Exposure to off-pump coronary artery bypass and beating heart surgery significantly correlated with future adoption of the technique by the cardiothoracic surgery residents. Cardiothoracic surgery residents in the lowest, middle, and highest terciles of exposure to off-pump coronary artery bypass and beating heart surgery plan to use these techniques 31%, 86%, and 75%, respectively, in selective cases when they are in independent practice. Conclusions: Over half of graduating cardiothoracic surgery residents do not feel comfortable with off-pump coronary artery bypass or beating heart surgery techniques. Exposure to these techniques in training correlates with comfort level and plans to use them in independent practice.
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Humanoid robots hold a decent advantage over wheeled robots because of their ability to mimic human exile. The presented paper proposes a novel strategy for trajectory planning in a cluttered terrain using the hybridized controller modeled on the basis of modified MANFIS (multiple adaptive neuro-fuzzy inference system) and MOSFO (multi-objective sunflower optimization) techniques. The controller works in a two-step mechanism. The input parameters, i.e., obstacle distances and target direction, are first fed to the MANFIS controller, which generates a steering angle in both directions of an obstacle to dodge it. The intermediate steering angles are obtained based on the training model. The final steering angle to avoid obstacles is selected based on the direction of the target and additional obstacles in the path. It is further works as input for the MOSFO technique, which provides the ultimate steering angle. Using the proposed technique, various simulations are carried out in the WEBOT simulator, which shows a deviation under 5% when the results are validated in real-time experiments, revealing the technique to be robust. To resolve the complication of providing preference to the robot during deadlock condition in multi-humanoids system, the dining philosopher controller is implemented. The efficiency of the proposed technique is examined through the comparisons with the default controller of NAO based on toques produces at various joints that present an average improvement of 6.12%, 7.05% and 15.04% in ankle, knee and hip, respectively. It is further compared against the existed navigational strategy in multiple robot systems that also displays an acceptable improvement in travel length. In comparison in reference to the existing controller, the proposed technique emerges to be a clear winner by portraying its superiority.