Case report: Innovative treatment for one metastatic thyroid-like follicular carcinoma of the kidney with ATM and POLE mutations.

Thyroid-like follicular renal cell carcinoma (TLFRCC), also known as thyroid-like follicular carcinoma of the kidney or thyroid follicular carcinoma like renal tumor, is an exceedingly rare variant of renal cell carcinoma that has only recently been acknowledged. This neoplasm exhibits a distinct follicular morphology resembling that of the thyroid gland. Immunohistochemical analysis reveals positive expression of PAX8, Vimentin, and EMA, while thyroid-specific markers TG and TTF1 are consistently absent. Furthermore, there is a notable absence of any concurrent thyroid pathology on clinical evaluation. Previous reports have suggested that TLFRCC is an indolent, slow-growing malignancy with infrequent metastatic potential. In this report, we present a case of TLFRCC characterized by remarkable ossification and widespread metastasis, including multifocal pulmonary lesions, involvement of the abdominal wall, and infiltration into the psoas muscle. To our knowledge, this represents only the third documented instance of distant metastasis in thyroid follicular renal carcinoma. The current case demonstrates a therapeutic approach that combines radiotherapy with the utilization of toripalimab, a programmed cell death 1 (PD-1) receptor inhibitor, and pazopanib. This treatment regimen was tailored based on comprehensive genomic profiling, which identified mutations in the POLE (catalytic subunit of DNA polymerase epsilon) and ATM (ataxia-telangiectasia mutated) genes, both of which have been implicated in the pathogenesis of various malignant tumors. These findings represent a novel discovery, as such mutations have never been reported in association with TLFRCC. Thus far, this therapeutic approach has proven to be the most efficacious option for treating metastatic TLFRCC among previously reported, and it also marks the first mention of the potential benefits of radiotherapy in managing this particular subtype of renal cell carcinoma.

Nerve trunk healing and neuroma formation after nerve transection injury.

The nerve trunk healing process of a transected peripheral nerve trunk is composed of angiogenesis, nerve fiber regeneration, and scarring. Nerve trunk healing and neuroma formation probably share identical molecular mediators and similar regulations. At the nerve transection site, angiogenesis is sufficient and necessary for nerve fiber regeneration. Angiogenesis and nerve fiber regeneration reveal a positive correlation in the early time. Scarring and nerve fiber regeneration show a negative correlation in the late phase. We hypothesize that anti-angiogenesis suppresses neuromas. Subsequently, we provide potential protocols to test our hypothesis. Finally, we recommend employing anti-angiogenic small-molecule protein kinase inhibitors to investigate nerve transection injuries.

The safety and efficacy of immunotherapy and palliative radiotherapy in patients with metastatic non-small cell lung cancer: a systematic review and meta-analysis of 13 prospective studies.

OBJECTIVE: Whether palliative RT (pRT) can influence the prognosis of mNSCLC patients who are treated with immune checkpoint inhibitors (ICIs) is still under debate. Therefore, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of pRT plus ICIs in mNSCLC patients. METHODS: PubMed, Cochrane, and Embase databases were searched, and only prospective studies and randomized controlled trials (RCTs) were included. All data were analyzed with Stata 14.0 and Review Manager Version 5.4 software. RESULTS: A total of 13 studies were included. The combined ORRs for the ICIs group, cRT plus ICIs group, and SBRT plus ICIs group were 0.22 (95% CI: 1.27, 4.04), 0.26 (95% CI: 0.04, 0.49), and 0.29 (95% CI: 0.17, 0.40), respectively. And PFS were 2.21 (95% CI: 1.71, 2.70), 4.63 (95% CI: 2.16, 7.09), and 7.38 (95% CI: 2.16, 12.60) months, respectively. OS was 5.96 (95% CI: 3.85, 8.07), 9.04 (95% CI: 6.49, 11.59), and 7.96 (95% CI: 4.02, 11.91) months for the above groups, respectively. For safety terms, patients receiving ICIs plus SBRT had an incidence of 5% (95% CI: 2%, 9%) for pneumonia. CONCLUSION: Patients with mNSCLC may benefit from the combination of ICIs and pRT therapy, but these findings need further validation.

Microfluidic Manipulation for Biomedical Applications in the Central and Peripheral Nervous Systems.

Physical injuries and neurodegenerative diseases often lead to irreversible damage to the organizational structure of the central nervous system (CNS) and peripheral nervous system (PNS), culminating in physiological malfunctions. Investigating these complex and diverse biological processes at the macro and micro levels will help to identify the cellular and molecular mechanisms associated with nerve degeneration and regeneration, thereby providing new options for the development of new therapeutic strategies for the functional recovery of the nervous system. Due to their distinct advantages, modern microfluidic platforms have significant potential for high-throughput cell and organoid cultures in vitro, the synthesis of a variety of tissue engineering scaffolds and drug carriers, and observing the delivery of drugs at the desired speed to the desired location in real time. In this review, we first introduce the types of nerve damage and the repair mechanisms of the CNS and PNS; then, we summarize the development of microfluidic platforms and their application in drug carriers. We also describe a variety of damage models, tissue engineering scaffolds, and drug carriers for nerve injury repair based on the application of microfluidic platforms. Finally, we discuss remaining challenges and future perspectives with regard to the promotion of nerve injury repair based on engineered microfluidic platform technology.

Targeted nano-delivery strategies for facilitating thrombolysis treatment in ischemic stroke.

Ischemic stroke is one of the major causes of severe disability and death worldwide. It is mainly caused by a sudden reduction in cerebral blood flow due to obstruction of the supplying vessel by thrombi and subsequent initiation of a complex cascade of pathophysiological changes, which ultimately lead to brain ischemia and even irreversible infarction. Thus, timely and effective thrombolysis therapy remains a mainstay for acute ischemic stroke treatment. Tissue plasminogen activator (tPA), the only thrombolytic agent approved globally, provides substantial benefits by exerting a fibrinolysis effect, recovering the blood supply in occluded vessels and, thereby, salvaging the ischemic tissue. However, the clinical application of tPA was limited because of a few unsolved issues, such as a narrow therapeutic window, hemorrhagic complications, and limited thrombolytic efficacy, especially, for large thrombi. With the prosperous development of nanotechnology, a series of targeted delivery strategies and nanocomposites have been extensively investigated for delivering thrombolytic agents to facilitate thrombolysis treatment. Excitingly, numerous novel attempts have been reported to be effective in extending the half-life, targeting the thrombus site, and improving the thrombolytic efficacy in preclinical models. This article begins with a brief introduction to ischemic stroke, then describes the current state of thrombolysis treatment and, finally, introduces the application of various nanotechnology-based strategies for targeted delivery of thrombolytic agents. Representative studies are reviewed according to diverse strategies and nano-formulations, with the aim of providing integrated and up-to-date information and to improve the development of thrombolysis treatment for stroke patients.

Vascularized Capitate Transposition for the Treatment of Stage IIIB Kienböck Disease.

PURPOSE: The treatment of Kienböck disease (KD) continues to be controversial. In this study, we report the long-term follow-up outcomes of patients who were diagnosed with stage IIIB KD treated with vascularized capitate transposition. METHODS: A total of 16 patients were retrospectively reviewed. Baseline clinical information was extracted from medical records, and wrist function was clinically evaluated, including x-ray images. RESULTS: At the final follow-up, wrist pain was severe in 0 patients, moderate in 2 patients, mild in 5 patients, and absent in 9 patients. The mean postoperative active flexion and extension of the affected wrist was significantly improved after surgery compared with before surgery. The postoperative and preoperative mean grip strength was 35 kg and 27 kg, respectively. The Disabilities of the Arm, Shoulder, and Hand score was significantly improved after surgery compared with before surgery. CONCLUSIONS: Vascularized capitate transposition for the treatment of Lichtman stage IIIB KD is feasible and associated with improvements in wrist function and pain. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Visualizing the Pharmacologic Preconditioning Effect of Botulinum Toxin Type A by Infrared Thermography in a Rat Pedicled Perforator Island Flap Model.

BACKGROUND: Surgical delay can improve flap viability, leading to vasodilation, neovascularization, and vessel reorganization. Experiments suggest a similar positive effect of botulinum toxin type A on pedicled flap viability. However, whether it may convert choke anastomoses into true anastomoses and how to identify the optimal timing for flap transfer remain unclear. METHODS: One hundred fifty-four Sprague-Dawley rats were divided into a control group, three saline injection groups, and three botulinum toxin type A injection groups defined by time of injection (2, 3, and 4 weeks before flap harvest). A pedicled 11 × 3-cm flap was marked on the unilateral dorsum of each rat. Before flap harvest, the flap donors were assessed by infrared thermal imaging, postmortem arteriography, immunohistochemical staining of CD31, and enzyme-linked immunosorbent assay. Flap survival area percentage was measured on postoperative day 7. RESULTS: In the control and saline groups, infrared thermography showed three independent white hotspots interspaced by red zones over flaps, whereas it presented a continuous white band in the botulinum toxin type A groups. There was a significant increase in flap survival area, flap surface temperatures, numbers of identifiable vessels in the choke zones, microvascular density, and vascular endothelial growth factor concentration in the botulinum toxin type A groups. CONCLUSIONS: Botulinum toxin type A can convert choke anastomoses into true anastomoses, and its preconditioning effect cannot increase over time; it is appropriate to choose the timing point when the infrared thermal images show a continuous white band existing over flaps for flap transfer.

Visualized identification of the maximal surgical delay effect in a rat flap model.

Currently, experimental evidence suggests that the surgical delay can increase flap survival area, but its effect may decrease if the optimal delay period is missed. The aim of this study is to establish a sensitive and objective modality based on the visualized and individualized infrared thermography for identifying the maximal surgical delay effect. A rectangular three-angiosome flap was designed on the unilateral dorsum of the rat. Ninety-six rats were randomly divided into six groups according to the various delay time. Both the relative temperature and the relative temperature ratio were measured by the infrared thermography. Arterial density, number of vessels >0.1 mm in diameter, microvessel density, VEGF concentration, and flap viability were measured. Receiving operating characteristic curve with the highest Youden-Index was used to detect and identify an optimal cutoff point of the relative temperature ratio in the maximal surgical delay effect. The criteria for identifying the flap maximum delay effect based on the infrared thermography included the surface of the postdelayed flaps presented white color (higher temperature) instead of the red and white pattern of the normal skin and the optimal cutoff point of the relative temperature ratio was ≥1.17 with a sensitivity of 84.6% and a specificity of 77.3%. Instead, the sensitivity and specificity of the conventional method based on the delay time were 38.5 and 90.9%, respectively. Infrared thermal imaging can accurately identify the maximum delay effect when combined with the relative temperature ratio.

Effect of Endogenous Vascular Endothelial Growth Factor on Flap Surgical Delay in a Rat Flap Model.

BACKGROUND: Experimental evidence suggests that endogenous vascular endothelial growth factor (VEGF) may play a major role in the surgical delay phenomenon. The purpose of this study was to investigate the effect of endogenous VEGF on flap surgical delay. METHODS: A total of 82 adult male Sprague-Dawley rats with an average weight of 330 g were used for these experiments. These experiments were then conducted in two parts. In part 1, 32 rats were used to assess the effectiveness of VEGF inhibitor through Western blot assay and enzyme-linked immunosorbent assay. In part 2, 50 rats were used to investigate the effect of VEGF on flap surgical delay by means of arteriography, histologic analysis, and flap viability. RESULTS: The VEGF protein inhibition ratio reached the maximum (approximately 91.6 percent) in 5 to 7 days. The number of transverse arteries and the number of vessels greater than 0.1 mm in diameter on the 3-day delay duration and the 6-day delay duration were significantly greater than those of the normal group. The number of transverse arteries and the number of vessels greater than 0.1 mm in diameter on the 6-day inhibition duration were not significantly changed compared with the normal group. Microvascular density on the 6-day delay duration obviously increased, whereas the 6-day inhibition duration was not significantly changed in comparison to the normal group. CONCLUSION: Endogenous VEGF is an initiating factor of the surgical delay effect by controlling choke vessel dilation and neovascularization within the choke zones.

Development of genetically engineered iNKT cells expressing TCRs specific for the M. tuberculosis 38-kDa antigen.

INTRODUCTION: The invariant natural killer T (iNKT) cell has been shown to play a central role in early stages immune responses against Mycobacterium tuberculosis (Mtb) infection, which become nonresponsive (anergic) and fails to control the growth of Mtb in patients with active tuberculosis. Enhancement of iNKT cell responses to Mtb antigens can help to resist infection. STUDY DESIGN AND METHODS: In the present study, an Mtb 38-kDa antigen-specific T cell receptor (TCR) was isolated from human CD8(+) T cells stimulated by 38-kDa antigen in vitro, and then transduced into primary iNKT cells by retrovirus vector. RESULTS: The TCR gene-modified iNKT cells are endowed with new features to behave as a conventional MHC class I restricted CD8(+) T lymphocyte by displaying specific antigen recognition and anti-Mtb antigen activity in vitro. At the same time, the engineered iNKT cells retaining its original capacity to be stimulated proliferation by non-protein antigens α-Gal-Cer. CONCLUSIONS: This work is the first attempt to engineer iNKT cells by exogenous TCR genes and demonstrated that iNKT cell, as well as CD4(+) and CD8(+) T cells, can be genetically engineered to confer them a defined and alternative specificity, which provides new insights into TCR gene therapy for tuberculosis patients, especially those infected with drug-resistant Mtb.

Limited T cell receptor repertoire diversity in tuberculosis patients correlates with clinical severity.

BACKGROUND: The importance of CD4⁺ and CD8⁺ T cells in protection against tuberculosis (TB) is well known, however, the association between changes to the T cell repertoire and disease presentation has never been analyzed. Characterization of T-cells in TB patients in previous study only analyzed the TCR ß chain and omitted analysis of the Vα family even though α chain also contribute to antigen recognition. Furthermore, limited information is available regarding the heterogeneity compartment and overall function of the T cells in TB patients as well as the common TCR structural features of Mtb antigen specific T cells among the vast numbers of TB patients. METHODOLOGY/PRINCIPAL FINDINGS: CDR3 spectratypes of CD4⁺ and CD8⁺ T cells were analyzed from 86 patients with TB exhibiting differing degrees of disease severity, and CDR3 spectratype complexity scoring system was used to characterize TCR repertoire diversity. TB patients with history of other chronic disease and other bacterial or viral infections were excluded for the study to decrease the likely contribution of TCRs specific to non-TB antigens as far as possible. Each patient was age-matched with a healthy donor group to control for age variability. Results showed that healthy controls had a normally diversified TCR repertoire while TB patients represented with restricted TCR repertoire. Patients with mild disease had the highest diversity of TCR repertoire while severely infected patients had the lowest, which suggest TCR repertoire diversity inversely correlates with disease severity. In addition, TB patients showed preferred usage of certain TCR types and have a bias in the usage of variable (V) and joining (J) gene segments and N nucleotide insertions. CONCLUSIONS/SIGNIFICANCE: Results from this study promote a better knowledge about the public characteristics of T cells among TB patients and provides new insight into the TCR repertoire associated with clinic presentation in TB patients.

Development of genetically engineered CD4+ and CD8+ T cells expressing TCRs specific for a M. tuberculosis 38-kDa antigen.

Cell-mediated immunity is critical to the clearance of Mycobacterium tuberculosis due to the primarily intracellular niche of this pathogen. Adoptive transfer of M. tuberculosis-specific effector T cells has been shown to confer immunity to M. tuberculosis-infected recipients resulting in M. tuberculosis clearance. However, it is difficult to generate sufficient numbers of M. tuberculosis antigen-specific T cells in a short time. Recent studies have developed T cell receptor (TCR) gene-modified T cells that allow for the rapid generation of large numbers of antigen-specific T cells. Many TCRs that target various tumor and viral antigens have now been isolated and shown to have functional activity. Nevertheless, TCRs specific for intracellular bacterial antigens (including M. tuberculosis antigens) have yet to be isolated and their functionality confirmed. We isolated M. tuberculosis 38-kDa antigen-specific HLA class I and class II-restricted TCRs and modified the TCR gene C regions by substituting nine amino acids with their murine TCR homologs (minimal murinization). Results showed that both wild-type and minimal murinized TCR genes were successfully cloned into retroviral vectors and transduced into primary CD4(+) and CD8(+) T cells and displayed anti-M. tuberculosis activity. As expected, minimal murinized TCRs displayed higher cell surface expression levels and stronger anti-M. tuberculosis activity than wild-type TCRs. To the best of our knowledge, this is the first report describing TCRs targeting M. tuberculosis antigens and this investigation provides the basis for future TCR gene-based immunotherapies that can be designed for the treatment of immunocompromised M. tuberculosis-infected patients.