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1.
J Comput Chem ; 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38979915

RESUMEN

The minimization of the commutator of the Fock and density matrices as the error matrix in the direct inversion of the iterative subspace (CDIIS) developed by Pulay is a powerful self-consistent field (SCF) acceleration technique for the construction of optimum Fock matrix, if initiated with a fair initial guess. In this work, we present an alternative minimized error matrix to the commutator in the CDIIS, namely the residual or the gradient of the energy-functional for a Slater determinant subject to the orthonormality constraints among orbitals, representing the search for a newly improved Fock matrix in the direction of the residual in the direct inversion of the iterative subspace (RDIIS). Implemented in the computational chemistry package GAMESS, the RDIIS is compared with the standard CDIIS and the second order SCF orbital optimization (SOSCF) for tested molecules started with a crude guess. As a result, the RDIIS stably and efficiently performs the SCF convergence acceleration. Furthermore, the RDIIS is considerably independent on the subspace size with the concentrated linear coefficients accounting proportionally for the Fock matrices close to the current iteration.

2.
Angew Chem Int Ed Engl ; : e202411255, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38980971

RESUMEN

Conversion-type electrode materials have gained massive research attention in sodium-ion batteries (SIBs), but their limited reversibility hampers practical use. Herein, we report a bifunctional nanoreactor to boost highly reversible sodium-ion storage, wherein a record-high reversible degree of 85.65% is achieved for MoS2 anodes. Composed of nitrogen-doped carbon-supported single atom Mn (NC-SAMn), this bifunctional nanoreactor concurrently confines active materials spatially and catalyzes reaction kinetics. In-situ/ex-situ characterizations including spectroscopy, microscopy, and electrochemistry, combined with theoretical simulations containing density functional theory and molecular dynamics, confirm that the NC-SAMn nanoreactors facilitate the electron/ion transfer, promote the distribution and interconnection of discharging products (Na2S/Mo), and reduce the Na2S decomposition barrier.As a result, the nanoreactor-promoted MoS2 anodes exhibit ultra-stable cycling with a capacity retention of 99.86% after 200 cycles in the full cell. This work demonstrates the superiority of bifunctional nanoreactors with two-dimensional confined and catalytic effects, providing a feasible approach to improve the reversibility for a wide range of conversion-type electrode materials, thereby enhancing the application potential for long-cycled SIBs.

3.
Int Arch Allergy Immunol ; : 1, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38991517

RESUMEN

INTRODUCTION: Rheumatoid arthritis (RA) combined with hashimoto thyroiditis (HT) is an important cause of various fatal comorbidities of RA. There is no precise conclusion about the cause of this disease. METHODS: Peripheral blood and synovial tissue were collected from healthy participants, patients with RA, and patients with both RA and HT. Immunofluorescence staining and Pearson correlation analysis were used to detect the levels of γδTCR and the correlation between IL-17 and p-STAT3, respectively. ELISA, chemiluminescence assays, qRT-PCR and Western blot were performed to detect the levels of IgG, IgM, IFN-γ, IL-1ß, TNF-α, Tg-Ab, Tpo-Ab, IL-17, IL-2, p-SATA3, and STAT3, respectively. RESULTS: There was increased proportion of γδT cells, IL-17, and p-STAT3 levels in RA and HT patients. IL-17 was positively correlated with p-STAT3. γδT cells significantly promoted the expression of IgG, Tg-Ab, Tpo-Ab, and IL-17. When γδT and human fibroblast-like synoviocytes (FLSs) were co-cultured, the levels of IL-2, IFN-γ, IL-1ß, TNF-α, and IL-17 were increased, and the IL-17/STAT3 signaling pathway was activated. When IL-17-silenced γδT cells and STAT3-silenced FLSs were co-cultured, the levels of IL-1ß and TNF-α in FLSs were significantly decreased. Furthermore, when STAT3-silenced FLSs were added to the co-culture medium of B cells and γδT cells, the levels of IL-1ß and TNF-α were also decreased significantly. CONCLUSION: γδT cells induced RA directly or by stimulating B cells to activate STAT3 through IL-17.

4.
PLoS One ; 19(7): e0304654, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38980889

RESUMEN

PURPOSE: This meta-analysis compared the efficacy and safety of Proximal Femoral Nail Antirotation (PFNA) and InterTan Nail in the treatment of intertrochanteric fractures. Given the high incidence of femoral intertrochanteric fractures in the elderly population and its impact on quality of life, choosing the most effective and safest surgical option is crucial. PFNA and InterTan are currently two commonly used techniques, but there is a lack of systematic evaluation comparing their safety and effectiveness. This study aims to fill this knowledge gap through Meta-analysis, providing clinicians with evidence-based treatment recommendations. MATERIALS AND METHODS: A computer search was used to search for published literature on PFNA and InterTan in the treatment of intertrochanteric fractures in PubMed (Medline), Web of Science, Embase, Cochrane Library (CENTRAL), Cinahl, CBM, and CNKI.A total of 853 related literatures were retrieved, and 15 literatures were finally included. Newcastle-Ottawa-Scale and Cochrane systematic review methodologies were used to assess the quality of the literature. Meta-analysis was performed using Review Manager 5.4 software, following data extraction. RESULTS: The comparison found that during the surgical treatment of intertrochanteric fractures, the operation time, fluoroscopy time, and blood loss in the PFNA group were significantly shorter than those in the InterTan group, and the difference was statistically significant. In terms of postoperative complication rates, the InterTan group had a significant advantage over the PFNA group. Shaft fracture, varus collapse, cut out, screw migration, and pain of hip and thigh were the most likely to occur in the PFNA group, and the differences were all statistically significant. In terms of postoperative efficacy, the results of the PFNA group and the InterTan group were comparable, and there was no significant differences. CONCLUSIONS: When selecting surgical techniques for the treatment of femoral intertrochanteric fractures, it is necessary to conduct individualized assessments based on the patient's overall health status, surgical tolerance, and post-operative recovery needs. For patients who cannot tolerate long-term surgery or are in poor physical condition, PFNA may be more appropriate. While for patients who can tolerate long-term surgery or have more complex conditions, InterTan may be more suitable.


Asunto(s)
Clavos Ortopédicos , Fracturas de Cadera , Humanos , Fracturas de Cadera/cirugía , Resultado del Tratamiento , Fijación Intramedular de Fracturas/métodos , Fijación Intramedular de Fracturas/instrumentación , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología
5.
Front Microbiol ; 15: 1400214, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38946900

RESUMEN

Background: The prevalence of pulmonary tuberculosis (PTB) as an infectious disease continues to contribute significantly to global mortality. According to recent studies, the gut microbiota of PTB patients and healthy controls (HCs) show significant disparities. However, the causal relationship between them has yet to be elucidated. Methods: We conducted a study using Mendelian Randomization (MR) to explore the potential causal link between gut microbiota and pulmonary tuberculosis (PTB). The summary statistics of the gut microbiota were acquired from the MiBioGen consortium, while data on PTB were sourced from pheweb.jp. A range of statistical methodologies were employed to evaluate causality, encompassing inverse variance weighting (IVW), MR-Egger, weighted median (WM), weighted model, and simple model. We utilized instrumental variables (IVs) that have a direct causal relationship with PTB to annotate SNPs, aiming to discover the genes harboring these genetic variants and uncover potential associations between host genes and the microbiome in patients with PTB. Results: Among the 196 bacterial traits in the gut microbiome, we have identified a total of three microbiomes that exhibit a significant association with PTB. The occurrence of Dorea (P = 0.0458, FDR-adjusted P = 0.0458) and Parasutterella (P = 0.0056, FDR-adjusted P = 0.0168) was linked to an elevated risk of PTB, while the presence of Lachnoclostridium (P = 0.0347, FDR-adjusted P = 0.0520) demonstrated a protective effect against PTB. Our reverse Two-Sample Mendelian Randomization (TSMR) analysis did not yield any evidence supporting the hypothesis of reverse causality from PTB to alterations in the intestinal flora. Conclusion: We have established a connection between the gut microbiota and PTB through gene prediction analysis, supporting the use of gut microecological therapy in managing PTB and paving the way for further understanding of how gut microbiota contributes to PTB's development.

7.
Nurs Open ; 11(7): e2240, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38989536

RESUMEN

AIM: To retrieve, analyse and summarize the relevant evidence on the prevention and management of bladder dysfunction in patients with cervical ancer after radical hysterectomy. DESIGN: Overview of systematic reviews. METHODS: 11 databases were searched for relevant studies from top to bottom according to the '6S' model of evidence-based resources. Two independent reviewers selected the articles, extracted the data and appraised the quality of the included reviews based on different types of evaluation tools. RESULTS: A total of 13 studies were identified, including four clinical consultants, four guidelines, four systematic reviews and one randomized controlled trial. 29 best evidence were summarized from five aspects, including definition, risk factors, assessment, prevention and management.


Asunto(s)
Histerectomía , Humanos , Histerectomía/efectos adversos , Femenino , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Factores de Riesgo , Enfermedades de la Vejiga Urinaria/prevención & control , Enfermedades de la Vejiga Urinaria/etiología
8.
J Nanobiotechnology ; 22(1): 388, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38956618

RESUMEN

BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent swine pathogen, which has caused adverse impact on the global swine industry for almost 30 years. However, due to the immune suppression caused by the virus and the genetic diversity in PRRSV, no virus-targeting broad neutralizing strategy has been successfully developed yet. Antiviral peptide and nanobody have attracted extensive attention with the ease in production and the efficacy in practice. In this study, four new fusion proteins named nanobody peptide conjugates (NPCs) were developed by combining PRRSV specific non-neutralizing nanobodies with CD163-derived peptides targeting the receptor binding domain (RBD) of PRRSV proteins. RESULTS: Four NPCs were successfully constructed using two nanobodies against PRRSV N and nsp9 individually, recombining with two antiviral peptides 4H7 or 8H2 from porcine CD163 respectively. All four NPCs demonstrated specific capability of binding to PRRSV and broad inhibitory effect against various lineages of PRRSV in a dose-dependent manner. NPCs interfere with the binding of the RBD of PRRSV proteins to CD163 in the PRRSV pre-attachment stage by CD163 epitope peptides in the assistance of Nb components. NPCs also suppress viral replication during the stage of post-attachment, and the inhibitory effects depend on the antiviral functions of Nb parts in NPCs, including the interference in long viral RNA synthesis, NF-κB and IFN-ß activation. Moreover, an interaction was predicted between aa K31 and T32 sites of neutralizing domain 4H7 of NPC-N/nsp9-4H7 and the motif 171NLRLTG176 of PRRSV GP2a. The motif 28SSS30 of neutralizing domain 8H2 of NPC-N/nsp9-8H2 could also form hydrogens to bind with the motif 152NAFLP156 of PRRSV GP3. The study provides valuable insights into the structural characteristics and potential functional implications of the RBD of PRRSV proteins. Finally, as indicated in a mouse model, NPC intranasally inoculated in vivo for 12-24 h sustains the significant neutralizing activity against PRRSV. These findings inspire the potential of NPC as a preventive measure to reduce the transmission risk in the host population against respiratory infectious agents like PRRSV. CONCLUSION: The aim of the current study was to develop a peptide based bioactive compound to neutralize various PRRSV strains. The new antiviral NPC (nanobody peptide conjugate) consists of a specific nanobody targeting the viral protein and a neutralizing CD163 epitope peptide for virus blocking and provides significant antiviral activity. The study will greatly promote the antiviral drug R&D against PRRSV and enlighten a new strategy against other viral diseases.


Asunto(s)
Anticuerpos Neutralizantes , Antígenos CD , Antígenos de Diferenciación Mielomonocítica , Péptidos , Virus del Síndrome Respiratorio y Reproductivo Porcino , Receptores de Superficie Celular , Anticuerpos de Dominio Único , Virus del Síndrome Respiratorio y Reproductivo Porcino/inmunología , Virus del Síndrome Respiratorio y Reproductivo Porcino/efectos de los fármacos , Animales , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/farmacología , Anticuerpos de Dominio Único/química , Porcinos , Antígenos de Diferenciación Mielomonocítica/inmunología , Antígenos de Diferenciación Mielomonocítica/metabolismo , Receptores de Superficie Celular/inmunología , Antígenos CD/inmunología , Antígenos CD/metabolismo , Anticuerpos Neutralizantes/inmunología , Péptidos/química , Péptidos/farmacología , Péptidos/inmunología , Síndrome Respiratorio y de la Reproducción Porcina/inmunología , Síndrome Respiratorio y de la Reproducción Porcina/prevención & control , Ratones , Replicación Viral/efectos de los fármacos , Línea Celular
9.
Front Oncol ; 14: 1430531, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39022588

RESUMEN

Background: Diffuse uterine leiomyomatosis (DUL) is a seldom-seen condition, with only a handful of cases of magnetic resonance imaging (MRI) findings documented. In clinical settings, it is often mistaken for multiple uterine leiomyomas due to a lack of adequate recognition of DUL. Objective: This study shows two instances of DUL, underscoring their MRI findings to improve preoperative diagnostic precision. Conclusion: For patients exhibiting multiple uterine leiomyomas with masses present in the parametrial and abdominal cavities, consideration should be given to diagnosing DUL with DPL. The discoveries outlined in this paper furnish insights that can assist in directing treatment choices.

11.
BMC Pregnancy Childbirth ; 24(1): 483, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39020280

RESUMEN

BACKGROUND: Hypercalcemia can be a rare contributor to acute pancreatitis (AP) in pregnancy. This is primarily due to primary hyperparathyroidism (PHPT), resulting from parathyroid carcinoma. We exhibited a case report to analyze the diagnosis and treatment during the onset of hypercalcemia-induced AP. CASE PRESENTATION: A 32-year-old primigravida presented with acute pancreatitis near full-term gestation. Following a cesarean delivery, there was a reduction in serum amylase and peripancreatic exudate, but her serum calcium concentrations persistently elevated over 4.0 mmol/L. Interventions to lower the hypercalcemia were only temporarily effective, until a high serum parathyroid hormone (PTH) concentration of 1404 pg/mL was detected. Ultrasound revealed a 31 mm × 24 mm hypoechoic oval nodule in the left lower lobe of the thyroid gland. She underwent a parathyroidectomy, resulting in a dramatic decrease in serum PTH level, from preoperative levels of 2051 pg/mL to 299 pg/mL just 20 minutes after removal. Similarly, her serum calcium declined from 3.82 mmol/L to 1.73 mmol/L within 24 hours postoperatively. The final histopathology suggested parathyroid carcinoma. CONCLUSION: When refractory hypercalcemia is present, serum PTH levels should be measured to determine PHPT. Parathyroidectomy is the optimal strategy for alleviating hypercalcemia and clarifying the underlying pathology.


Asunto(s)
Hipercalcemia , Pancreatitis , Neoplasias de las Paratiroides , Paratiroidectomía , Complicaciones Neoplásicas del Embarazo , Tercer Trimestre del Embarazo , Humanos , Femenino , Hipercalcemia/etiología , Hipercalcemia/sangre , Neoplasias de las Paratiroides/complicaciones , Neoplasias de las Paratiroides/cirugía , Embarazo , Adulto , Pancreatitis/etiología , Pancreatitis/complicaciones , Pancreatitis/sangre , Complicaciones Neoplásicas del Embarazo/cirugía , Hormona Paratiroidea/sangre , Hiperparatiroidismo Primario/cirugía , Hiperparatiroidismo Primario/complicaciones , Hiperparatiroidismo Primario/sangre , Cesárea , Calcio/sangre
12.
CNS Neurosci Ther ; 30(7): e14854, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39021297

RESUMEN

AIMS: This study aimed to evaluate the safety of reducing or withdrawing anti-seizure medications (ASMs) in a cohort comprising both adults and children with drug-resistant epilepsy (DRE) undergoing ketogenic diet therapy (KDT). METHODS: We conducted a comprehensive analysis of clinical profiles in adults and children with DRE who had adhered to KDT for at least 6 months. Successful withdrawal or reduction of an ASM was defined as discontinuation or dose reduction without subsequent resumption or increase and without initiation of any new ASM throughout the entire follow-up period. Changes in the ASM load were calculated specifically for adult patients. RESULTS: The study enrolled 56 participants (34 children and 22 adults) with DRE, with 64.3% achieving successful withdrawal of at least one ASM. The probability of ASM withdrawal remained consistent for children (64.7%) versus adults (63.6%), as well as for responders (62.5%) versus non-responders (68.8%), and it was not associated with other clinical factors. Early ASM reduction (including withdrawal) after diet initiation occurred in 15 patients (26.8%), with treatment outcomes comparable to those of the remaining participants. Among the 22 adults, the mean values of ASM load reduced by 24.5%, with a similar magnitude observed for responders (24.2%) versus non-responders (25.1%). In addition, adults tend to have a slower elevation in serum ketone levels compared to children. CONCLUSION: This study demonstrates the safe achievability of ASM withdrawal through KDT in most patients with DRE, irrespective of age or seizure frequency reduction.


Asunto(s)
Anticonvulsivantes , Dieta Cetogénica , Epilepsia Refractaria , Humanos , Dieta Cetogénica/métodos , Epilepsia Refractaria/dietoterapia , Epilepsia Refractaria/tratamiento farmacológico , Masculino , Femenino , Adulto , Niño , Anticonvulsivantes/uso terapéutico , Adolescente , Adulto Joven , Preescolar , Persona de Mediana Edad , Resultado del Tratamiento , Estudios de Cohortes , Estudios de Seguimiento , Estudios Retrospectivos
13.
J Adv Nurs ; 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39041430

RESUMEN

AIM: A skin tear (ST) is a common skin injury that is often misdiagnosed or overlooked. This study examined the current state of nurses' ST knowledge and its influencing factors. DESIGN: A national cross-sectional survey combined with a quantitative analysis was used to provide evidence of poor ST knowledge among nurses and its influencing factors. METHODS: An electronic questionnaire survey was conducted among 1293 nurses from 32 hospitals in 18 provinces across China, including a General Information Questionnaire, ST Knowledge Assessment Instrument (OASES) and a Self-directed Learning Competence Scale for Nurses (SLCS-N). RESULTS: The mean OASES score was 9.51 ± 3.15, with a score rate of 47.55%. Pearson's correlation analysis showed positive correlations, ranging from none to strong, between every dimension in the OASES and from strong to extremely strong between every dimension in the SLCS-N. Multivariate analysis revealed multiple independent factors influencing ST knowledge, such as hospital tier, specialized nurses in wound/ostomy/incontinence care, participation in training for wound/ostomy/incontinence management, willingness to undergo ST training, self-assessed grade in ST care and the degree of emphasis of managers. CONCLUSION: ST knowledge status was generally poor among nurses nationwide. Managers should establish a comprehensive and specialized curriculum-based system, develop evidence-based standardized nursing processes, and provide tailored training programs to address nurses' unique characteristics and individualized needs, thereby enhancing their proficiency in ST-related knowledge and skills. IMPACT: This study is the first to identify a poor level of ST knowledge among nurses nationwide, particularly in the four dimensions of risk assessment: prevention, treatment, classification, and observation. Based on the findings regarding demographic factors and ST experiences, an integrated management system and educational program should be implemented to improve nurses' awareness and knowledge in this field. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contributions.

14.
Ann Neurol ; 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38877824

RESUMEN

OBJECTIVE: The aim of this study was to explore the pathogenesis of CLCN6-related disease and to assess whether its Cl-/H+-exchange activity is crucial for the biological role of ClC-6. METHODS: We performed whole-exome sequencing on a girl with development delay, intractable epilepsy, behavioral abnormities, retinal dysfunction, progressive brain atrophy, suggestive of neuronal ceroid lipofuscinoses (NCLs). We generated and analyzed the first knock-in mouse model of a patient variant (p.E200A) and compared it with a Clcn6-/- mouse model. Additional functional tests were performed with heterologous expression of mutant ClC-6. RESULTS: We identified a de novo heterozygous p.E200A variant in the proband. Expression of disease-causing ClC-6E200A or ClC-6Y553C mutants blocked autophagic flux and activated transcription factors EB (TFEB) and E3 (TFE3), leading to autophagic vesicle and cholesterol accumulation. Such alterations were absent with a transport-deficient ClC-6E267A mutant. Clcn6E200A/+ mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC-6E200A, but not loss of ClC-6 in Clcn6-/- mice, increased lysosomal biogenesis by suppressing mTORC1-TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in Clcn6E200A/+ brain, while only lipid storage was found in Clcn6-/- brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss. INTERPRETATION: CLCN6 is a novel genetic cause of NCLs, highlighting the importance of considering CLCN6 mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl- transport from H+ countertransport in the E200A mutant has a dominant effect on the autophagic/lysosomal pathway. ANN NEUROL 2024.

16.
Arch Biochem Biophys ; 758: 110063, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38880321

RESUMEN

To investigate the potential molecular mechanism of miR-34a in Sjögren's syndrome (SS). Transmission electron microscopy was used to observe the salivary gland tissues of mild and severe SS patients. SS mouse model was constructed and injected with miR-34a antagonist. HSGE cells were transfected with miR-34a mimic. Starbase predicted miR-34a binding sites and validated them with dual-luciferase reporter assays. Immunohistochemistry, HE staining, CCK-8, TUNEL assay, flow cytometry, immunofluorescence and Western Blot were used to investigate the effects of miR-34a on NF-κB signaling and mitochondrial pathway of apoptosis in HSGE cells. Severe SS patients showed obvious mitochondrial damage and apoptosis in salivary glands. MiR-34a was overexpressed and NF-κB signaling is activated in salivary glands of severe SS patients. Inhibition of miR-34a alleviated salivary gland injury in SS mice, as well as inhibited the activation of NF-κB signaling and mitochondrial pathway of apoptosis. In conclusion, miR-34a promoted NF-κB signaling by targeting IκBα, thereby causing mitochondrial pathway apoptosis and aggravating SS-induced salivary gland damage.


Asunto(s)
Apoptosis , Células Epiteliales , MicroARNs , Mitocondrias , FN-kappa B , Glándulas Salivales , Transducción de Señal , Síndrome de Sjögren , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Mitocondrias/metabolismo , FN-kappa B/metabolismo , Glándulas Salivales/metabolismo , Glándulas Salivales/patología , Animales , Células Epiteliales/metabolismo , Células Epiteliales/patología , Ratones , Síndrome de Sjögren/metabolismo , Síndrome de Sjögren/genética , Síndrome de Sjögren/patología , Femenino , Línea Celular , Masculino , Persona de Mediana Edad
17.
Cancer Med ; 13(12): e7224, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38888366

RESUMEN

BACKGROUND: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. METHODS: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. RESULTS: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively). CONCLUSIONS: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Fluorouracilo , Inhibidores de Puntos de Control Inmunológico , Humanos , Masculino , Femenino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Proyectos Piloto , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Reparación de la Incompatibilidad de ADN , Adulto , Inestabilidad de Microsatélites , Oxaliplatino/uso terapéutico , Oxaliplatino/administración & dosificación , Terapia Neoadyuvante/métodos , Microambiente Tumoral/inmunología , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Resultado del Tratamiento
18.
Mikrochim Acta ; 191(7): 364, 2024 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-38831034

RESUMEN

CdIn2S4 and zinc tetrakis(4-carboxyphenyl)porphyrin (ZnTCPP) were synthesized by hydrothermal method, and an organic dye-sensitized inorganic semiconductor ZnTCPP/CdIn2S4 type II heterojunction was constructed on a fluorine-doped tin oxide (FTO) substrate electrode. A sandwich immunostructure for signal-attenuation photoelectrochemical (PEC) detection of cardiac troponin I (cTnI) was constructed using the ZnTCPP/CdIn2S4/FTO photoanode and a horseradish peroxidase (HRP)-ZnFe2O4-Ab2-bovine serum albumin (BSA) immunolabeling complex. The bioenzyme HRP and the HRP-like nanozyme ZnFe2O4 can co-catalyze the oxidation of 4-chloro-1-naphthol (4-CN) by H2O2 to produce an insoluble precipitate on the photoanode, thus notably reducing the anodic photocurrent for quantitative determination of cTnI. Under the optimal conditions, the photocurrent at 0 V vs. SCE in 0.1 M phosphate buffer solution (pH 7.40) containing 0.1 M ascorbic acid was linear with the logarithm of cTnI concentration from 500 fg mL-1 to 50.0 ng mL-1, and the limit of detection (LOD, S/N = 3) is 0.15 pg mL-1. Spiked recoveries were 95.1% ~ 104% for assay of cTnI in human serum samples.


Asunto(s)
Técnicas Electroquímicas , Límite de Detección , Compuestos de Estaño , Troponina I , Troponina I/sangre , Humanos , Técnicas Electroquímicas/métodos , Inmunoensayo/métodos , Compuestos de Estaño/química , Catálisis , Peroxidasa de Rábano Silvestre/química , Naftoles/química , Metaloporfirinas/química , Electrodos , Peróxido de Hidrógeno/química , Albúmina Sérica Bovina/química , Procesos Fotoquímicos , Animales , Técnicas Biosensibles/métodos , Semiconductores , Bovinos , Sulfuros/química , Porfirinas/química
19.
mSphere ; : e0036224, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38860771

RESUMEN

Eggs, an important part of a healthy daily diet, can protect chicken embryo development due to the shell barrier and various antibacterial components within the egg white. Our previous study demonstrated that Salmonella Pullorum, highly adapted to chickens, can survive in the egg white and, therefore, be passed to newly hatched chicks. However, the survival strategy of Salmonella Pullorum in antibacterial conditions remains unknown. The overall transcripts in the egg white showed a large-scale shift compared to LB broth. The expression of common response genes and pathways, such as those involved in iron uptake, biotin biosynthesis, and virulence, was significantly changed, consistent with the other transovarial transmission serovar Enteritidis. Notably, membrane stress response, amino acid metabolism, and carbohydrate metabolism were specifically affected. Additional upregulated functionally relevant genes (JI728_13095, JI728_13100, JI728_17960, JI728_10085, JI728_15605, and nhaA) as mutants confirmed the susceptible phenotype. Furthermore, fim deletion resulted in an increased survival capacity in the egg white, consistent with the downregulated expression. The second-round RNA-Seq analysis of the Δfim mutant in the egg white revealed significantly upregulated genes compared with the wild type in the egg white responsible for energy metabolism located on the hyc and hyp operons regulated by FhlA, indicating the Δfim mutant cannot receive enough oxygen and switched to fermentative growth due to its inability to attach to the albumen surface. Together, this study provides a first estimate of the global transcriptional response of Salmonella Pullorum under antibacterial egg white and highlights the new potential role of fim deletion in optimizing energy metabolism pathways that may assist vertical transmission. IMPORTANCE: Pullorum disease, causing serious embryo death and chick mortality, results in substantial economic losses worldwide due to transovarial transmission. Egg-borne outbreaks are frequently reported in many countries. The present study has filled the knowledge gap regarding how the specific chicken-adapted pathogen Salmonella Pullorum behaves within the challenging environment of egg white. The deletion of the fim fimbrial system can increase survival in the albumen, possibly by reprogramming metabolism-related gene products, which reveals a new adaptive strategy of pathogens. Moreover, the comparison, including previous research on Salmonella Enteritidis, capable of vertical transmission, aims to provide diversified data sets in the field and further help to implement reasonable and effective measures to improve both food safety and animal health.

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