Endoplasmic reticulum stress-related gene model predicts prognosis and guides therapies in lung adenocarcinoma.

BACKGROUND: The prognosis and survival of lung adenocarcinoma (LUAD) patients are still not promising despite recent breakthroughs in treatment. Endoplasmic reticulum stress (ERS) is a self-protective mechanism resulting from an imbalance in quality control of unfolded proteins when cells are stressed, which plays an active role in lung cancer development, but the relationship between ERS and the pathological characteristics and clinical prognosis of LUAD patients remains unclear. METHODS: LASSO and Cox regression were applied based on sequencing information to construct the model, which was validated to be robust. The risk scores of the patients were calculated using the formula provided by the model, and the patients were divided into high and low-risk groups according to the median cut-off of risk scores. Cox regression analysis identifies independent prognostic factors for these patients, and enrichment analysis of prognosis-related genes was also performed. The relationship between risk scores and tumor mutation burden (TMB), cancer stem cell index, and drug sensitivity was explored. RESULTS: We constructed a 13-gene prognostic model for LUAD patients. Patients in the high-risk group had worse overall survival, lower immune score and ESTIMATE score, higher TMB, higher cancer stem cell index, and higher sensitivity to conventional chemotherapeutic agents. In addition, we constructed a nomogram that predicts 5-year survival in LUAD patients, which helps clinicians to foresee the prognosis from a new perspective. CONCLUSIONS: Our results highlight the association of ERS with LUAD and the potential use of ERS in guiding treatment.

An Electroconductive Hydrogel Scaffold with Injectability and Biodegradability to Manipulate Neural Stem Cells for Enhancing Spinal Cord Injury Repair.

Spinal cord injury (SCI) generally leads to long-term functional deficits and is difficult to repair spontaneously. Many biological scaffold materials and stem cell treatment strategies have been explored, but very little research focused on the method of combining exogenous neural stem cells (NSCs) with a biodegradable conductive hydrogel scaffold. Here, a NSC loaded conductive hydrogel scaffold (named ICH/NSCs) was assembled by amino-modified gelatin (NH2-Gelatin) and aniline tetramer grafted oxidized hyaluronic acid (AT-OHA). Desirably, the well-conducting ICH/NSCs can be simply injected into the target site of SCI for establishing a good electrical signal pathway of cells, and the proper degradation cycle facilitates new nerve growth. In vitro experiments indicated that the inherent electroactive microenvironment of the hydrogel could better manipulate the differentiation of NSCs into neurons and inhibit the formation of glial cells and scars. Collectively, the ICH/NSC scaffold has successfully stimulated the recovery of SCI and may provide a promising treatment strategy for SCI repair.

Shape memory of a polymer grating surface fabricated by two-beam interference lithography.

Switchable and reversible optical elements have potential applications in self-adaptive optics. Shape-memory polymer devices with adaptive properties could be easily switched under environment or field stimuli. Here, the laser beam interference technique was used to realize the periodic grating structures of the shape-memory polymer, and memory and recovery of the grating structures were performed. A one-dimensional grating structure was fabricated from dual-beam interference lithography of a nanosecond laser and underwent pressure in a condition of 195°C. The vertical height of the grating was reduced, and the diffraction light was weakened. When the sample was cooled down to room temperature, the morphology of the grating could be kept. After raising the ambient temperature of the sample to 120°C, the morphology of the grating was recovered to the original state, which realized the shape-memory function.

Hydrogel Composites with Different Dimensional Nanoparticles for Bone Regeneration.

The treatment of large segmental bone defects and complex types of fractures caused by trauma, inflammation, or tumor resection is still a challenge in the field of orthopedics. Various natural or synthetic biological materials used in clinical applications cannot fully replicate the structure and performance of raw bone. This highlights how to endow materials with multiple functions and biological properties, which is a problem that needs to be solved in practical applications. Hydrogels with outstanding biocompatibility, for their casting into any shape, size, or form, are suitable for different forms of bone defects. Therefore, they have been used in regenerative medicine more widely. In this review, versatile hydrogels are compounded with nanoparticles of different dimensions, and many desirable features of these materials in bone regeneration are introduced, including drug delivery, cell factor vehicle, cell scaffolds, which have potential in bone regeneration applications. The combination of hydrogels and nanoparticles of different dimensions encourages better filling of bone defect areas and has higher adaptability. This is due to the minimally invasive properties of the material and ability to match irregular defects. These biological characteristics make composite hydrogels with different dimensional nanoparticles become one of the most attractive options for bone regeneration materials.

Mediastinal Rosai-Dorfman Disease with KRAS mutation case report and literature review.

BACKGROUND: Rosai-Dorfman Disease (RDD) is a rare self-limiting histiocytosis, more prevalent in children and young adults. It typically manifests as painless bilateral massive cervical lymphadenopathy but may also extend to extra-nodal sites, with intrathoracic RDD noted in 2% of cases. Distinguishing mediastinal RDD from thymoma on imaging poses challenges, underscoring the reliance on pathological features and immunohistochemical staining for diagnosis. CASE PRESENTATION: Patient, male, 33 years old, underwent lung a CT revealing an enlarged round soft tissue shadow in the anterior superior mediastinum, compared to a year ago. Surgical resection removed the entire mass, thymus, and part of the pericardium, confirming RDD on pathology. Genetic testing using second-generation testing technology identified a KRAS gene point mutation. CONCLUSIONS: No established treatment protocol currently exists for this disease. However, as genetic mutation research progresses, a novel therapeutic avenue is emerging: targeted therapy integrated with surgical interventions.

Exploring the multifaceted effects of Interleukin-1 in lung cancer: From tumor development to immune modulation.

Lung cancer, acknowledged as one of the most fatal cancers globally, faces limited treatment options on an international scale. The success of clinical treatment is impeded by challenges such as late diagnosis, restricted treatment alternatives, relapse, and the emergence of drug resistance. This predicament has led to a saturation point in lung cancer treatment, prompting a rapid shift in focus towards the tumor microenvironment (TME) as a pivotal area in cancer research. Within the TME, Interleukin-1 (IL-1) is abundantly present, originating from immune cells, tissue stromal cells, and tumor cells. IL-1's induction of pro-inflammatory mediators and chemokines establishes an inflammatory milieu influencing tumor occurrence, development, and the interaction between tumors and the host immune system. Notably, IL-1 expression in the TME exhibits characteristics such as staging, tissue specificity, and functional pluripotency. This comprehensive review aims to delve into the impact of IL-1 on lung cancer, encompassing aspects of occurrence, invasion, metastasis, immunosuppression, and immune surveillance. The ultimate goal is to propose a novel treatment approach, considering the intricate dynamics of IL-1 within the TME.

Multifunctional nanoprobe for multi-mode imaging and diagnosis of metastatic prostate cancer.

The high incidence and complex subtypes of prostate cancer put forward higher requirements for accurate diagnosis. Furthermore, advanced prostate cancer is prone to metastasis. Single biological imaging mode faces a challenge of sensitive and fast bioimaging of metastasic prostate cancer. Thus, exploring a nanoprobe with multi-mode imaging function has an important impact on preoperative imaging and intraoperative visualization guide of metastatic prostate cancer. Herein, based on the optical properties and X-ray attenuation capability of Au nanodots as well as the slow electronic relaxation of Gd3+, we designed and fabricated the multifunctional nanoprobe Au/Gd nanodots for multi-mode imaging and accurate diagnosis of bone metastatic prostate cancer. The results showed that multiple imaging modes complement each other to achieve high-precision of metastasic prostate cancer detection and accurately guide treatment. In addition, in vitro/vivo experiments showed that Au/Gd nanodots had good biocompatibility and biosafety. Therefore, the prepared multifunctional nanoprobe may provide new strategies and insights for precise diagnosis of metastatic prostate cancer in clinical practice.

Au/Mn nanodot platform for in vivo CT/MRI/FI multimodal bioimaging and photothermal therapy against tongue cancer.

Surgical resection is the main method for oral tongue squamous cell carcinoma (OTSCC) treatment. However, the oral physiological function and aesthetics may be seriously damaged during the operation with a high risk of recurrence. Therefore, it is important to develop an alternative strategy with precise guidance for OTSCC treatment. Herein, multifunctional Au/Mn nanodots (NDs) are designed and synthesized. They can perform multimodal bioimaging, including computed tomography (CT) and magnetic resonance imaging (MRI) simultaneously, and exhibit bright near-infrared fluorescence imaging (FI) for navigation, and even integrate photothermal therapy (PTT) property. The localization of OTSCC relies on visual and tactile cues of surgeons while lacking noninvasive pretreament labeling and guidance. Au/Mn NDs provide CT/MRI imaging, giving two means of accurate positioning pretherapy. Meanwhile, the fluorescence of the Au/Mn NDs in the near-infrared region (NIR) is beneficial for noninvasive labeling and intuitive observation with the naked eye to determine the tumor boundary during PTT. Further, Au/Mn NDs showed excellent results in ablating tumors in vivo. Above all, the Au/Mn NDs provide a key platform for multimodal bioimaging and PTT in a single nanoagent, which demonstrated attractive performance for OTSCC treatment.

Prognostic necroptosis-related gene signature aids immunotherapy in lung adenocarcinoma.

Background: Necroptosis is a phenomenon of cellular necrosis resulting from cell membrane rupture by the corresponding activation of Receptor Interacting Protein Kinase 3 (RIPK3) and Mixed Lineage Kinase domain-Like protein (MLKL) under programmed regulation. It is reported that necroptosis is closely related to the development of tumors, but the prognostic role and biological function of necroptosis in lung adenocarcinoma (LUAD), the most important cause of cancer-related deaths, is still obscure. Methods: In this study, we constructed a prognostic Necroptosis-related gene signature based on the RNA transcription data of LUAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases as well as the corresponding clinical information. Kaplan-Meier analysis, receiver operating characteristic (ROC), and Cox regression were made to validate and evaluate the model. We analyzed the immune landscape in LUAD and the relationship between the signature and immunotherapy regimens. Results: Five genes (RIPK3, MLKL, TLR2, TNFRSF1A, and ALDH2) were used to construct the prognostic signature, and patients were divided into high and low-risk groups in line with the risk score. Cox regression showed that risk score was an independent prognostic factor. Nomogram was created for predicting the survival rate of LUAD patients. Patients in high and low-risk groups have different tumor purity, tumor immunogenicity, and different sensitivity to common antitumor drugs. Conclusion: Our results highlight the association of necroptosis with LUAD and its potential use in guiding immunotherapy.

Case report: Incomplete laceration of the right middle lobar bronchus due to blunt chest trauma: An unusual pattern and attentions.

Tracheobronchial ruptures caused by blunt chest trauma are rarely encountered but may be life-threatening. It is even rarer when the rupture is in the right middle lobe bronchus. Here we present a case of incomplete laceration of the right middle lobe bronchus after blunt trauma, which could easily be overlooked because of the absence of obvious symptoms. A 58-year-old man suffered multiple traumas after being attacked by cattle, closed chest drainage was promptly performed in the local hospital for bilateral hemopneumothorax. Three days later, the patient was transferred to our center for urgent exploratory thoracic surgery due to persistent hemothorax. We did not diagnose bronchial injury even after a bedside emergency bronchoscopy due to the adherence of bloody secretions and sputum crusts. It was not until a repeat chest CT 4 days after the initial surgery that we suspected an incomplete right middle lobe bronchial laceration, which was confirmed by postoperative bronchoscopy. The patient eventually underwent right middle lobe lung resection for a deep and wide bronchial laceration and recovered well. Clinicians should be fully aware of the possibility of this condition after blunt chest trauma and make good use of CT and bronchoscopy to help with diagnosis and treatment.

Prognostic value of tumor size in thymic epithelial tumors: A systematic review and meta-analysis.

BACKGROUND: Whether the size of thymic epithelial tumors (TETs) has an impact on prognosis has long been a controversial issue. Our study was designed to investigate the value of tumor size in the prognosis (overall survival (OS) and relapse-free survival) of patients with TETs. METHODS: We searched the databases such as PubMed, EMBASE, Web of Science, and clinical trials registration system for articles illustrating the impact of tumor size on survival data in TETs patients. We did a meta-analysis for OS and relapse-free survival. RESULTS: We recruited 9 studies in our meta-analysis. Our study illustrates that TETs patients with small tumor size had better relapse-free survival (hazard ratio = 1.66, 95% confidence interval 1.18-2.35, P = .004) and OS (hazard ratio = 1.93, 95% confidence interval 1.30-2.80, P = .001) in comparison to patients with large tumor size. CONCLUSIONS: In conclusion, the results of our meta-analysis showed that TET size was significantly associated with overall and relapse-free survival of patients, with relatively small tumors tending to have a better prognosis.

STAT3 and p63 in the Regulation of Cancer Stemness.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor with many important functions in normal and transformed cells. STAT3 regulatory activities are highly complex as they are involved in various signaling pathways in different cell types under different conditions. Biologically, STAT3 is a regulative factor for normal and cancer stem cells (CSCs). Tumor protein p63 (p63), a member of the p53 protein family, is involved in these biological processes and is also physically and functionally associated with STAT3. STAT3 activation occurs during various aspects of carcinogenesis, including regulation of CSCs properties. In combination with p63, STAT3 is a possible biological marker of CSCs and a major regulator of maintenance of stemness in CSCs. We summarized the STAT3 functions and regulation and its role in CSC properties and highlight how these are affected by its associations with p63.

Gold nanodots with stable red fluorescence for rapid dual-mode imaging of spinal cord and injury monitoring.

Spinal cord injury is one of the most devastating complications of spinal surgery, often resulting in numbness, pain or paralysis. Minor injuries in the spinal cord are hard to be identified and existing imaging modalities are unable to provide intraoperative monitoring. Monitoring pathological change at the site of injury is a key factor in staging and treatment decision making as well as prognosis of spinal cord injury. Herein, we offer the fluorescence imaging with intraoperative visualization and detection accuracy for bioimaging to resolve the problem. A novel red fluophore AuNDs caped with glutathione is prepared, which exhibits some advantages such as ultra-small size, negligible biotoxicity, superior water solubility and great biocompatibility. AuNDs fluorophore especially exhibit both of a remarkable photoluminescence stability and high attenuation coefficient to X-rays. In addition, AuNDs can be used as CT contrast agent for spinal cord, which avoid the high toxicity and weak CT signal of traditional iodine contrast. After intradural injection into the spinal cord, AuNDs are transported through the flow of cerebrospinal fluid and bound to the spinal cord parenchyma. not only the bioimage of the entire spinal cord can be achieved as quick as 15 min, but they are also particularly beneficial to long-term imaging of complex physiological environments in vivo, with negligible quenching. Comparing from the bright red fluorescence in adjacent normal spinal cord sites, there is almost no fluorescence in spinal cord at the areas of the injury. We suggest that AuNDs are unable to enter the injury sites of necrosis and ischemia, which promote a different contrast imaging from the normal one. The bright red fluorescence of the AuNDs significantly overcome the restriction of the blue autofluorescence of the biological tissues, providing a clear boundary for observation of the thin spinal cord injury. As a result, we developed the AuNDs with fluorescent and CT dual-mode bioimaging capability to clearly and effectively diagnose spinal cord injury, which are expected to provide a novel visualization imaging regent for clinical use.

Tumor-Associated Regulatory T Cell Expression of LAIR2 Is Prognostic in Lung Adenocarcinoma.

Cancer development requires a permissive microenvironment that is shaped by interactions between tumor cells, stroma, and the surrounding matrix. As collagen receptors, the leukocyte-associated immunoglobulin-like receptor (LAIR) family allows the immune system to interact with the extracellular matrix. However, little is known about their role in regulating tumor immunity and cancer progression. METHODS: Genetic analysis of resected human lung adenocarcinoma was correlated to clinical-pathological characteristics, gene ontologies, and single cell RNA sequencing (scRNASeq). LAIR2 production was determined in subsets of immune cells isolated from blood leukocytes and lung adenocarcinoma tumor. Functional assays were used to determine the role of LAIR2 in tumorigenesis. RESULTS: LAIR2 expression was adversely prognostic in lung adenocarcinoma. LAIR2 was preferentially produced by activated CD4+ T cells and enhanced in vitro tumor invasion into collagen. scRNASeq analysis of tumor infiltrating T cells revealed that LAIR2 expression co-localized with FOXP3 expressing cells and shared a transcriptional signature with tumor-associated regulatory T (Treg) cells. A CD4+ LAIR2+ Treg gene signature was prognostically significant in the TCGA dataset (n = 439; hazard ratio (HR) = 1.37; 95% confidence interval (CI), 1.05-1.77, p = 0.018) and validated in NCI Director's Challenge lung adenocarcinoma dataset (n = 488; HR = 1.54; 95% CI, 1.14-2.09, p = 0.0045). CONCLUSIONS: Our data support a role for LAIR2 in lung adenocarcinoma tumorigenesis and identify a CD4+ LAIR2+ Treg gene signature in lung adenocarcinoma prognosis. LAIR2 provides a novel target for development of immunotherapies.

Developing Allogeneic Double-Negative T Cells as a Novel Off-the-Shelf Adoptive Cellular Therapy for Cancer.

PURPOSE: To expand clinical-grade healthy donor-derived double-negative T cells (DNT) to a therapeutically relevant number and characterize their potential to be used as an "off-the-shelf" adoptive cellular therapy (ACT) against cancers. EXPERIMENTAL DESIGN: We developed methods to expand DNTs under GMP conditions and characterized their surface molecule expression pattern using flow cytometry-based high-throughput screening. We investigated the off-the-shelf potential of clinical-grade DNTs by assessing their cytotoxicity against various cancer types and their off-tumor toxicity in vitro and in xenograft models and determining the effect of cryopreservation under GMP conditions on cell viability and cytotoxicity. Further, we determined the susceptibility of DNTs to conventional allogeneic T cells in vitro and in vivo. RESULTS: Clinical-grade DNTs expanded 1,558 ± 795.5-fold in 17 days with >90% purity. Expanded DNTs showed potent in vitro cytotoxic activity against various cancer types in a donor-unrestricted manner. DNTs enhanced the survival of mice infused with a lethal dose of EBV-LCL and significantly reduced leukemia engraftment in xenograft models. Expanded DNTs cryopreserved using GMP-compliant reagents maintained viability and anticancer functions for at least 600 days. Live allogeneic DNTs did not induce cytotoxicity of alloreactive CD8+ T cells in vitro, and coinfusion of DNTs with peripheral blood mononuclear cells (PBMC) from a different donor into mice resulted in coengraftment of DNTs and PBMC-derived allogeneic conventional T cells in the absence of cytotoxicity toward DNTs, suggesting the lack of host-versus-graft reaction. CONCLUSIONS: We have established a method to generate therapeutic numbers of clinical-grade DNTs that fulfill the requirements of an off-the-shelf ACT.

Targeting late-stage non-small cell lung cancer with a combination of DNT cellular therapy and PD-1 checkpoint blockade.

BACKGROUND: Though immune checkpoint blockade (ICB) against PD-1 has shown success in the treatment of lung cancer, not all patients respond. We have previously shown that adoptive transfer of double negative T (DNT) cells expanded from healthy donors can target leukemia but their role in treating established lung cancer is not clear. Here we explore the role of human DNT cells in targeting late-stage established lung cancer either alone or in combination with Nivolumab (anti-PD-1 antibody) and describe underlying mechanisms. METHODS: DNT cells from resected lung cancer tissue of patients were analyzed by flow cytometry to determine their infiltration and PD-1 expression. Expansion capacity and anti-tumor function of lung cancer patient and healthy donor DNT cells were compared. Late-stage lung cancer xenograft models were developed to determine the anti-tumor effect of DNT cells alone or in combination with anti-PD-1 antibody, and the level of tumor-infiltrating DNT cells was quantified by histology and characterized by flow cytometry. RESULTS: Patient-derived tumor infiltrating lymphocytes contained a lower frequency of DNT cells with a higher expression of PD-1 relative to normal lung tissue. Ex vivo expanded patient- and healthy donor-derived DNT cells showed similar levels of cytotoxicity against lung cancer cells in vitro. Healthy donor-derived DNT cells significantly inhibited the growth of late-stage lung cancer xenografts, which was further augmented by anti-PD-1 through increased DNT cell tumor infiltration. CONCLUSION: This study supports the use of DNT cells for adoptive cellular therapy against lung cancer either alone or in combination with anti-PD-1.

Human double negative T cells target lung cancer via ligand-dependent mechanisms that can be enhanced by IL-15.

BACKGROUND: The advents of novel immunotherapies have revolutionized the treatment of cancer. Adoptive cellular therapies using chimeric antigen receptor T (CAR-T) cells have achieved remarkable clinical responses in B cell leukemia and lymphoma but the effect on solid tumors including lung cancer is limited. Here we present data on the therapeutic potential of allogeneic CD3+CD4-CD8- double negative T (DNT) cells as a new cellular therapy for the treatment of lung cancer and underlying mechanisms. METHODS: DNTs were enriched and expanded ex vivo from healthy donors and phenotyped by flow cytometry. Functionally, their cytotoxicity was determined against primary and established non-small-cell lung cancer (NSCLC) cell lines in vitro or through in vivo adoptive transfer into xenograft models. Mechanistic analysis was performed using blocking antibodies against various cell surface and soluble markers. Furthermore, the role of IL-15 on DNT function was determined. RESULTS: We demonstrated that ex vivo expanded DNTs can effectively lyse various human NSCLC cells in vitro and inhibit tumor growth in xenograft models. Expanded DNTs have a cytotoxic phenotype, as they express NKp30, NKG2D, DNAM-1, membrane TRAIL (mTRAIL), perforin and granzyme B, and secrete IFNγ and soluble TRAIL (sTRAIL). DNT-mediated cytotoxicity was dependent on a combination of tumor-expressed ligands for NKG2D, DNAM-1, NKp30 and/or receptors for TRAIL, which differ among different NSCLC cell lines. Furthermore, stimulation of DNTs with IL-15 increased expression of effector molecules on DNTs, their TRAIL production and cytotoxicity against NSCLC in vitro and in vivo. CONCLUSION: Healthy donor-derived DNTs can target NSCLC in vitro and in vivo. DNTs recognize tumors via innate receptors which can be up-regulated by IL-15. DNTs have the potential to be used as a novel adoptive cell therapy for lung cancer either alone or in combination with IL-15.

Pooled analysis for surgical treatment for isolated adrenal metastasis and non-small cell lung cancer.

OBJECTIVES: This systematic review and pooled analysis investigated outcomes and prognostic factors in Non-small-cell lung cancer (NSCLC) patients who underwent surgical treatment for an isolated adrenal metastasis and the primary NSCLC. METHODS: A literature search of PubMed, Embase and Cochrane Library databases was conducted for relevant retrospective studies in patients with NSCLC and isolated adrenal metastatic lesions treated with lobectomy or pneumonectomy and adrenalectomy. Outcome measures were overall, 1-, 2- and 5-year survival rates stratified by synchronous versus metachronous adrenal metastasis and according to lymph node status, pathology and relative location of the metastasis to the primary tumour. Kaplan-Meier survival curves were generated and differences in survival were assessed by a log-rank test. RESULTS: Thirteen studies involving 98 patients were included in this analysis. The median overall survival was 18 months, and the 1-, 2- and 5-year survival rates were 66.5, 40.5 and 28.2%, respectively. Patients with metachronous adrenal metastasis had a significantly better prognosis than patients with synchronous adrenal metastasis (P < 0.05). Patients classified as negative for lymph node metastasis had a significantly better prognosis than patients classified as positive for lymph node metastasis (P < 0.05). Pathology (squamous carcinoma versus adenocarcinoma) and the relative location of the metastasis to the primary tumour (ipsilateral adrenal metastasis or contralateral adrenal metastasis) had no significant influence on prognosis. CONCLUSIONS: NSCLC patients with isolated adrenal metastasis undergoing surgical treatment for the primary tumour and adrenal metastasis could achieve a significant survival benefit, especially if they have metachronous adrenal metastasis or are negative for lymph node metastasis.