Real-world data analysis of immune checkpoint inhibitors in stage III-IV adenocarcinoma and squamous cell carcinoma.

BACKGROUND: This study was designed to investigate the clinical application, efficacy, and safety of immune checkpoint inhibitors (ICIs) in the treatment of lung cancer in the real world. METHODS: A retrospective, observational analysis was conducted on patients treated with ICIs in four tertiary hospitals in the region from January 2015 to March 2021, to evaluate the clinical efficacy of ICIs single-agent or combined chemotherapy and anti-vascular drugs in the first-line or second-line treatment of patients with lung cancer. RESULTS: Three hundred and fifteen patients were enrolled in this study. In patients with stage III-IV adenocarcinoma and Squamous cell carcinoma, the objective response rate (ORR) and disease control rate (DCR) were 35.5% (87/245) and 93.5% (229/245), respectively, the median progression-free survival (PFS) was 10.8 months, and the median overall survival (OS) was not reached. A total of 132 patients received ICIs as the first-line treatment, the median treatment cycle was 8 cycles (2-20 cycles), the short-term efficacy ORR was 38.6%, DCR was 93.9%, and the median PFS was 11.4 months. One hundred thirteen patients received ICIs treatment as second-line treatment, the median treatment cycle was five cycles (2-10 cycles), the short-term efficacy ORR was 31.9%, DCR was 92.9%, and the median PFS was 10.0 months. There were no statistically significant differences in ORR, DCR, or median PFS with ICIs as the first-line treatment compared with the second-line treatment(P > 0.05). The results of subgroup analysis showed that Eastern Cooperative Oncology Group performance status (ECOG PS), epidermal growth factor receptor (EGFR) mutation status, pathological type and number of treatment lines were not correlated with median PFS(P > 0.05). However, there were statistically significant differences in programmed death-ligand 1(PD-L1) expression, corticosteroid interference, and antibiotic (Abx) treatment among all groups (P < 0.05). In terms of safety, the overall incidence of adverse reactions in 315 patients was 62.5%, and the incidence of immune-related adverse events (irAEs) was 13.7%. Grade 1-2 and 3-4 incidence of adverse events were 34.9 and 27.65%, respectively. There were four patients who experienced fatal irAEs, two cases were liver damage leading to liver failure, one case was immune related pneumonia, and one case was immune related myocarditis. CONCLUSION: In the real world, ICIs has a good effect on patients with lung cancer and significantly improves ORR and PFS.

A hybrid solid electrolyte for solid-state sodium ion batteries with good cycle performance.

A ceramic in polymer hybrid solid electrolyte (HSE) based on a poly vinylidene fluoride-hexafluoropropylene (PVDF-HFP) polymer comprising Na3Zr2Si2PO12 (NASICON) ceramic particles was prepared by a simple solution casting method followed by activation in a liquid electrolyte. The prepared HSE exhibits good flexibility, high ionic conductivity of 2.25 × 10-3 S cm-1 at room temperature (RT), and good interface stability. The carbon coated sodium vanadium phosphate (Na3V2(PO4)3/C) cathode was synthesized by the sol-gel method and assembled into batteries with different electrolytes. The batteries based on HSE exhibit better electrochemical performance than that of NASICON ceramic solid electrolytes, which delivers a reversible capacity of 98 mAh · g-1 at 0.2 C and exhibits good capacity retention of 85% after 175 cycles at 0.5 C. Not only does the HSE inherit great flexibility, but also exhibits good interfacial contact with electrodes. The schematic diagram of Na-ion conductivity in ceramic, polymer and HSE was illustrated to demonstrate the sodium ion transport mechanism. The HSE with high ionic conductivity and good flexibility for interfacial contact with electrodes shall provide a designing strategy for different solid-state batteries.

A trehalose biosynthetic enzyme doubles as an osmotic stress sensor to regulate bacterial morphogenesis.

The dissacharide trehalose is an important intracellular osmoprotectant and the OtsA/B pathway is the principal pathway for trehalose biosynthesis in a wide range of bacterial species. Scaffolding proteins and other cytoskeletal elements play an essential role in morphogenetic processes in bacteria. Here we describe how OtsA, in addition to its role in trehalose biosynthesis, functions as an osmotic stress sensor to regulate cell morphology in Arthrobacter strain A3. In response to osmotic stress, this and other Arthrobacter species undergo a transition from bacillary to myceloid growth. An otsA null mutant exhibits constitutive myceloid growth. Osmotic stress leads to a depletion of trehalose-6-phosphate, the product of the OtsA enzyme, and experimental depletion of this metabolite also leads to constitutive myceloid growth independent of OtsA function. In vitro analyses indicate that OtsA can self-assemble into protein networks, promoted by trehalose-6-phosphate, a property that is not shared by the equivalent enzyme from E. coli, despite the latter's enzymatic activity when expressed in Arthrobacter. This, and the localization of the protein in non-stressed cells at the mid-cell and poles, indicates that OtsA from Arthrobacter likely functions as a cytoskeletal element regulating cell morphology. Recruiting a biosynthetic enzyme for this morphogenetic function represents an intriguing adaptation in bacteria that can survive in extreme environments.

Wolf's Isotopic Response after Herpes Zoster Infection: A Study of 24 New Cases and Literature Review.

Wolf's isotopic response refers to the occurrence of a new skin disease at the exact site of an unrelated skin disease that had previously healed. Various cutaneous lesions have been described after herpes zoster. This study included 24 patients with Wolf's isotopic response after herpes zoster infection, which presented as manifestations ranging from inflammatory disease to carcinoma. Histopathological examinations in 12 patients and immunohistochemical analyses in 10 patients allowed exploration of secondary microscopic changes in the lesions. CD4+/CD8+ T-cell ratios were normal and infiltrating cells included mast cells, eosinophils, and tumour cells. Our study has described additional patients with confirmed Wolf's isotopic response following herpes zoster infection; moreover, it has extended the spectrum of Wolf's isotopic response to include impetigo. We suggest Wolf's isotopic response classification categories for herpes zoster-associated Wolf's isotopic response. Additionally, clinicians should consider the possibilities of different diseases in Wolf's isotopic response, especially malignancies.

Efficacy of irinotecan-based chemotherapy after exposure to an anti-PD-1 antibody in patients with advanced esophageal squamous cell carcinoma.

OBJECTIVE: Several anti-programmed cell death 1 (anti-PD-1) antibodies have demonstrated potential efficacy in the treatment of advanced esophageal squamous cell cancer (ESCC). However, the response to subsequent chemotherapy after the failure of PD-1 blockade in ESCC patients has not been reported, and the optimal sequencing of immunotherapy and chemotherapy remains controversial. The aim of the present study was to evaluate responses to irinotecan-based subsequent chemotherapy in advanced ESCC patients who had progressed after treatment with camrelizumab (SHR-1210), a novel anti-PD-1 antibody. METHODS: We retrospectively reviewed the medical records of patients with advanced ESCC treated with camrelizumab at a single institution. Consecutive patients who received subsequent irinotecan-based chemotherapy were selected for data collection and analysis. RESULTS: Overall, a total of 28 patients were included. All patients had received at least two lines of systemic treatment prior to irinotecan salvage. The most common regimen that was administered after PD-1 blockade was irinotecan in combination with 5-fluorouracil (5-Fu) (or its derivatives), which was given to 19 patients. The objective response rate (ORR) and disease control rate (DCR) were 17.9% (5/28) and 64.3% (18/28), respectively, with 5 (17.9%) patients achieving a partial response and 13 (46.4%) having stable disease. The median progression-free survival (PFS) was 3.18 [95% confidence interval (95% CI), 2.48-3.88] months and the median overall survival (OS) was 6.23 (95% CI, 4.71-7.75) months. No new safety issues, either immune-related or otherwise, were observed. CONCLUSIONS: Our results suggested that the response to irinotecan-based chemotherapy after PD-1 blockade in advanced ESCC patients appeared similar to that previously observed in patients who had not received PD-1 antibodies, and further study in larger cohorts or randomized trials is warranted to verify our observation.

Screening of differentially expressed proteins from syncytiotrophoblast for severe early-onset preeclampsia in women with gestational diabetes mellitus using tandem mass tag quantitative proteomics.

BACKGROUND: Previous studies have revealed that women with gestational diabetes mellitus (GDM) have an increased risk of developing preeclampsia (PE). The possible reason is the abnormal lipid metabolism caused by GDM that leads to dysfunction of vascular endothelial cells and atherosclerosis, resulting in the onset of PE. However, studies focusing on the pathogenesis of PE in syncytiotrophoblast of GDM patients are lacking. This study aimed to compare differentially expressed proteins from syncytiotrophoblast between women with GDM and women with GDM with subsequently developed PE. METHODS: Syncytiotrophoblast samples were obtained from pregnant women immediately after delivery. To explore the protein expression changes of syncytiotrophoblast that might explain the pathogenesis of PE in women with GDM, quantitative proteomics was performed using tandem mass tag (TMT) isobaric tags and liquid chromatography-tandem mass spectrometry. Bioinformatics analysis was performed to enrich the biological processes that these differentially expressed proteins were involved in. RESULTS: A total of 28,234 unique peptides and 4140 proteins were identified in all samples. Among them, 23 differentially expressed proteins were identified between patients with GDM and patients with GDM with subsequently developed PE. Therein, 11 proteins were upregulated and 12 proteins were downregulated. Two relative proteins (FLT1 and PABPC4) were independently verified using immunoblotting analysis. Bioinformatic results indicated that the onset of PE in patients with GDM is a multifactorial disorder, involving factors such as apoptosis, transcriptional misregulation, oxidative stress, lipid metabolism, cell infiltration and migration, and angiogenesis. CONCLUSION: These results indicated that the inadequacy of endometrium infiltration, angiogenic disorder, and oxidative stress in syncytiotrophoblast are more likely to occur in patients with GDM and may be the potential mechanisms leading to such patients secondarily developing severe early-onset PE.

Resection of melanocytic nevi as a potential treatment of anti-NMDAR encephalitis patients without tumor: report of three cases.

The most common underlying tumor associated with anti-N-methyl D-aspartate-receptor (NMDAR) encephalitis is ovarian teratoma. Resection of the underlying tumor may decrease exposure of autoantigen and make for faster response of immunotherapy and less relapse frequency. Similar to teratoma, expression of NMDAR in human epidermal melanocytes was suspected recently. The dense melanocytes in melanocytic nevus may serve as potential autoantigens and are prone to increase relapse frequency in the tumor-negative patients. Three patients with confirmed diagnosis of anti-NMDAR encephalitis were described here. They shared common features that the screening tests for an ovarian teratoma or other tumors were all negative, while they were found to have prominent melanocytic nevi on the skin and resection of the nevi likely played a positive effect on their persistent recovery. This is a report on treatment of anti-NMDAR encephalitis patients without underlying tumor through resection of melanocytic nevi. More clinical and experimental investigations are needed to prove its validity.

Spectrum of Clinical, Neuroimaging, and Cerebrospinal Fluid Features of Adult Neurocutaneous Melanocytosis.

BACKGROUND: Neurocutaneous melanocytosis (NCM) is a poorly understood disease due to its rarity. This study aimed to summarize the characteristics of adult NCM and improve the awareness of this disease. METHODS: The clinical data of 13 adult patients with NCM were retrospectively reviewed, including neuroimages, cerebrospinal fluid (CSF), and histological features. RESULTS: There were 9 males and 4 females. The mean age at symptom onset was 36.5 years. The initial symptoms included intracranial hypertension in 8 patients and seizure in 4 patients. Ten patients had large and/or multiple congenital melanocytic nevi. MRI revealed hydrocephalus and diffuse thickening of the leptomeninges with T1 shortening in all patients. Post-contrast T1-weighted images showed diffuse linear enhancement of the leptomeninges. Lumbar punctures showed increased open pressure, and elevated protein levels and decreased glucose concentrations in CSF. Cells with intracytoplasmic coarse black granules were found in the CSF and were positive for S100, HMB45, and vimentin. Histopathology of the cutaneous lesions and meninges showed melanocytes but no evidence of malignant melanoma. CONCLUSION: Adult NCM patients present a diversity of clinical manifestations. Brain MRI showing diffuse thickening of the leptomeninges with T1 shortening is useful in diagnosing NCM. Heterocellular melanin may be of great value for early diagnosis of NCM in challenging cases.

[Effects of Danshensu on bone formation in ovariectomized rats].

Objective: To investigate the effects of Danshensu on bone formation in ovariectomized rats.Methods: Thirty female SD rats were randomly divided into three groups with 10 rats in each:blank control group, model control group and Danshensu group. The osteoporosis model was induced by bilateral ovariectomy and rats in Danshensu group were fed with Danshensu 12.5 mg·kg-1·d-1 by gavage after ostroporosis model induced. All animals were sacrificed after 90 days. The bone mineral density (BMD) of the whole body, femur and lumbar vertebra was measured by dual energy X-ray absorptiometry. The biomechanical properties of femur were measured by AG-IS mechanical universal testing machine. Serum osteocalcin and bone alkaline phosphates (BALP) levels were measured by ELISA. The number of osteoblasts of proximal femoral metaphysis was counted with light microscopy after HE staining. Results: Compared with blank control group, BMD, biomechanical properties of femur, serum osteocalcin and BALP levels and the number of osteoblasts were decreased in model control group (P<0.05 or P<0.01). While compared with model control group, BMDs of the whole body, femur and lumbar vertebra, the elastic modulus, maximum load, yield strength, breaking point load of femur, the serum levels of osteocalcin and BALP, and the number of osteoblasts were significantly improved in Danshensu group (P<0.05 or P<0.01). Conclusion: Danshensu can improve bone quality by increasing bone density, improving biomechanical properties, promoting the expression of osteogenesis-related factors, and increasing the number of osteoblasts.

Anti-NMDAR encephalitis after resection of melanocytic nevi: report of two cases.

BACKGROUND: Encephalitis with antibodies against N-methyl D-aspartate receptor (NMDAR) is recognized as a group of antibody-mediated neuropsychiatric syndromes, which occurs with and without a tumor association. Neoplasm may contribute to the pathogenesis of Anti-NMDAR encephalitis in tumor-positive patients. However, the underlying causes in tumor-negative patients are largely unknown. This is the first report, of which we are aware, of two cases of anti-NMDAR encephalitis after the resection of melanocytic nevus. CASE PRESENTATION: We describe 2 female patients in their 20s confirmed with anti-NMDAR encephalitis. They shared two points in common: About several weeks (2 weeks and 5 weeks respectively) before the initial symptom, both of them underwent a resection of melanocytic nevi; the screening tests for an ovarian teratoma and other tumors were all negative. A 25 year-old woman presented with seizure, psychiatric symptoms and behavioral change for 2 weeks. Electroencephalogram indicated electrographic seizures. Anti-NMDAR antibodies were all positive in the cerebrospinal fluid and serum. Her symptoms relieved gradually after the treatment with steroids and mycophenolate mofetil. Another patient admitted to our hospital with psychosis, behavioral change and complex partial seizure over a period of 5 months. Electroencephalogram demonstrated generalized slow activities. High titres of anti-NMDAR antibodies were both detected in the cerebrospinal fluid and serum. She responded well to the first-line immunotherapy and got substantial recovery. CONCLUSION: Our cases provided an observational link between anti-NMDAR encephalitis and resection of nevi. We postulate that the exposure of certain antigen on nevus cell caused by nevi excision, which might be NMDA receptor or other mimic cross-reactive antigens, may trigger an autoimmune response resulting in encephalitis. This suggested a potential site of antigen exposure triggering the immune response in non-tumor associated anti-NMDAR encephalitis, which may lend support to elucidating the underlying immunopathological mechanisms. Further studies are expected for investigating the expression of NMDA receptor on nevus cell and evaluating the validity of this hypothesis.

Cloning and characterization of a novel caspase-8-like gene in Crassostrea gigas.

Cysteine-dependent aspartate-directed proteases, or caspases, play key roles in apoptosis and immune defense. In this study, we cloned the first caspase-8-like gene (CgCaspase8-2) identified in the pacific oyster, Crassostrea gigas. The 2572-bp cDNA encodes a putative protein of 714 amino acids that contains two tandem death effector domains (DEDs) at the N-terminal, and P20 and P10 domains at the C-terminal. The conserved pentapeptide motif QACQG was also identified in the deduced CgCaspase8-2 protein. Phylogenetic analysis indicated that CgCaspase8-2 was clustered with initiator caspases in the invertebrate subgroup, but the similarity between CgCaspase8-2 and other invertebrate caspase-8s was low. CgCaspase8-2 protein was localized in the cytoplasm, and over-expression of CgCaspase8-2 in HEK293T cells induced cell death, suggesting a role in apoptosis. Quantitative real-time PCR results demonstrated that CgCaspase8-2 was widely expressed in various tissues and developmental stages, with the highest CgCaspase8-2 expression levels detected in hemolymph and the blastula stage. Furthermore, CgCaspase8-2 transcripts showed no change in response to a bacterial challenge but exhibited notable up-regulation post-poly (I:C) challenge, suggesting that CgCaspase8-2 is specifically involved in immune responses against viruses. In summary, CgCaspase8-2 is involved in both apoptotic and immune function.

Causes of changes in carotid intima-media thickness: a literature review.

Atherosclerosis causes significant morbidity and mortality. Carotid intima-media thickness (CIMT) predicts future cardiovascular and ischaemic stroke incidence. CIMT, a measure of atherosclerotic disease, can be reliably determined in vivo by carotid ultrasound. In this review, we determined that CIMT is associated with traditional cardiovascular risk factors such as age, sex, race, smoking, alcohol consumption, habitual endurance exercise, blood pressure, dyslipidemia, dietary patterns, risk-lowering drug therapy, glycemia, hyperuricemia, obesity-related anthropometric parameters, obesity and obesity-related diseases. We also found that CIMT is associated with novel risk factors, including heredity, certain genotypic indices, anthropometric cardiovascular parameters, rheumatoid arthritis, immunological diseases, inflammatory cytokines, lipid peroxidation, anthropometric hemocyte parameters, infectious diseases, vitamin D, matrix metalloproteinases, and other novel factors and diseases. However, the conclusions are inconsonant; the underlying causes of these associations remain to be further explored.

Alternative splicing and immune response of Crassostrea gigas tumor necrosis factor receptor-associated factor 3.

Diverse alternative splicing isoforms play an important role in immune diversity and specificity. Their role in molluscan host-defense is however poorly understood. We characterized two alternative isoforms of tumor necrosis factor receptor-associated factor 3 (TRAF3) in the Pacific oyster, Crassostrea gigas, which were named CgTRAF3-S and CgTRAF3-L. An intron was retained in CgTRAF3-L, introducing a premature termination codon. Comparison and phylogenetic analysis revealed that CgTRAF3 shared a higher identity with other species, suggesting the conservation of the two gene transcripts. Quantitative real-time PCR was performed and the expression levels of CgTRAF3 isoforms were found to be significantly changed after Vibrio anguillarum and ostreid herpesvirus 1 challenges. These two isoforms represented contrary trends, indicating that CgTRAF3-L might function as a negative regulator of CgTRAF3-S. We also investigated the expression level of the transcripts of the two CgTRAF3 isoforms, following the silence of C. gigas mitochondrial anti-viral signaling protein like gene (CgMAVS-like). We concluded that CgTRAF3 might be involved in a MAVS-mediated immune signaling pathway. This study suggests that CgTRAF3 may be a response to bacterial and viral stimulation and that the two isoforms may be involved in immune response pathways. It is also possible that the two alternative splicing isoforms could be inter-coordinated and may promote survival of these oysters under immune stress conditions.

[Clinical characteristics of drug hypersensitivity syndrome in 10 patients].

OBJECTIVE: To characterize the clinical characteristics of drug hypersensitivity syndrome (DHS). METHODS: The clinical characteristics of 10 DHS patients admitted into our hospital were analyzed retrospectively. And the occurrence patterns of DHS were summarized. RESULTS: There were 4 males and 6 females with an age range of 17 to 66 years. Suspected drugs were anticonvulsants (n = 5), allopurinol (n = 2), antibiotics (n = 1), acetaminophen (n = 1) and unknown (n = 1). All cases developed skin rashes with fever within 14 to 60 days (n = 10). Lymphadenopathy was observed (n = 6). Morbilliform eruption was most common skin rash (n = 6); facial swelling was also appeared (n = 7). Eosinophilia was observed in all cases (n = 10). Liver involvement was common (n = 9). Autoimmune antibodies abnormality was uncommon; viral infection was complication in several cases. Glucocorticoids were applied in all cases (n = 10), 3 severe cases were administrated with intravenous immunoglobulin (IVIg). The clinical outcomes included discharging with recovery (n = 7), later diagnosed of non-Hodgkin lymphoma (n = 2) and in-hospital death (n = 1). CONCLUSIONS: The clinical manifestations of DHS are complicated. And the common reactive drugs include anticonvulsants, allopurinol, antiinflammatory drugs and antibiotics. Some cases may be misdiagnosed and long-term follow-ups are required.

Dark Current Reduction and Performance Improvements in Graphene/Silicon Heterojunction Photodetectors Obtained Using a Non-Stoichiometric HfOx Thin Oxide Layer.

Graphene/silicon heterojunction photodetectors suffer from a high dark current due to the high surface states and low barrier height at the interface, which limits their application. In this study, we introduce an HfOx interfacial layer via magnetron sputtering to address this issue. With this new structure, the dark current is reduced by six times under a bias voltage of -2 V. Under 460 nm illumination, the responsivity is 0.228A/W, the detectivity is 1.15 × 1011 cmHz1/2W-1, and the noise equivalent power is 8.75 × 10-5 pW/Hz1/2, demonstrating an excellent weak light detection capability. Additionally, the oxygen vacancies in the HfOx interfacial layer provide a conductive channel for charge carriers, resulting in a 2.03-fold increase in photocurrent and an external quantum efficiency of 76.5%. The photodetector maintains good photoresponse ability at a low bias voltage. This work showcases the outstanding performance of HfOx films as interfacial layer materials and provides a new solution for high-performance photodetectors, as well as a new path to improve the photovoltaic conversion efficiency of solar cells.