Pyruvate maintains and enhances the pro-inflammatory response of microglia caused by glucose deficiency in early stroke.

Pro-inflammatory microglia mainly rely on glycolysis to maintain cytokine production during ischemia, accompanied by an increase in inducible nitric oxide synthase (iNOS) and monocarboxylate transporter 1 (MCT1). The role of energy metabolism in the pro-inflammatory response of microglia is currently unclear. In this study, we tested the response of microglia in mice after cerebral ischemia and simulated an energy environment in vitro using low glucose culture medium. The research results indicate that the expression levels of iNOS and arginase 1 (ARG1) increase in the ischemic mouse brain, but the upregulation of MCT1 expression is mainly present in iNOS positive microglia. In microglia exposed to low glucose conditions, iNOS and MCT1 levels increased, while ARG1 levels decreased. Under the same conditions, knocking down MCT1 in microglia leads to a decrease in iNOS levels, while overexpression of MCT1 leads to the opposite result. The use of NF-κB inhibitors reduced the expression levels of iNOS and MCT1 in microglia. In summary, our data indicate that pyruvate maintains and enhances the NF-κB regulated pro-inflammatory response of microglia induced by low glucose.

Acute renal failure after kidney transplantation due to mizoribine-induced ureteral stones.

INTRODUCTION: Mizoribine (MZR) is used to prevent rejection reactions after kidney transplantation and increase the risk of hyperuricemia. There is a lack of reports of MZR-induced ureteral stones after kidney transplantation. The surgery treatment of ureteral stones in transplanted kidney is a challenging clinical issue that should only be performed by experienced urologists at professional centers. It is very important to have a thorough understanding of the patient's medical history, analyze the causes of stone formation, and choose a reasonable treatment plan based on the characteristics of the stones. The case report is aim to emphasize the recognition of the possibility of mizoribine-induced ureteral uric acid stones in transplanted kidney and to avoid unnecessary surgery. CASE PRESENTATION: A patient after kidney transplantation was diagnosed with acute renal failure caused by ureteral stones. The medical history, CT images of the renal graft, the results of laboratory test and stone composition analysis were provided. Based on medical history and laboratory test results, it was determined that the ureteral stones of renal graft was induced by MZR. To our best knowledge, this is the first report of MZR-induced stones in transplanted kidney and ureters. It was completely cured by urinary alkalinization, avoiding surgery treatment. We summarize the characteristics, treatment and methods for preventing the formation of uric acid stones of patients with MZR. CONCLUSION: By analyze our case report, it shows that acute renal failure with ureteral stones after kidney transplantation can caused by MZR. Urinary alkalinization for MZR induced uric acid stones is simple and effective.

Achieving Efficient CO2 Electrolysis to CO by Local Coordination Manipulation of Nickel Single-Atom Catalysts.

Selective electroreduction of CO2 to C1 feed gas provides an attractive avenue to store intermittent renewable energy. However, most of the CO2-to-CO catalysts are designed from the perspective of structural reconstruction, and it is challenging to precisely design a meaningful confining microenvironment for active sites on the support. Herein, we report a local sulfur doping method to precisely tune the electronic structure of an isolated asymmetric nickel-nitrogen-sulfur motif (Ni1-NSC). Our Ni1-NSC catalyst presents >99% faradaic efficiency for CO2-to-CO under a high current density of -320 mA cm-2. In situ attenuated total reflection surface-enhanced infrared absorption spectroscopy and differential electrochemical mass spectrometry indicated that the asymmetric sites show a significantly weaker binding strength of *CO and a lower kinetic overpotential for CO2-to-CO. Further theoretical analysis revealed that the enhanced CO2 reduction reaction performance of Ni1-NSC was mainly due to the effectively decreased intermediate activation energy.

Poorly Controlled Diabetes Mellitus Increases the Risk of Deaths and Castration-Resistance in Locally Advanced Prostate Cancer Patients.

The association between DM and prostate cancer progression remains controversial. Previous studies mainly focused on early stage prostate cancer patients. We aimed to study the association between DM and prostate cancer progression in locally advanced prostate cancer patients. 598 locally advanced prostate cancer patients in a top tertiary hospital in China between 2012 and 2021 were divided into three groups based on the postoperative average HbA1c level. The follow-up time is 46.96 ± 27.07 months. Three hundred and forty-eight (58.2%) were normal glucose, 175 (29.3%) were moderate glucose, and 75 (12.5%) were high glucose. Higher postoperative-average HbA1c was associated with poorer OS, PCSM, and PSA-RFS. We concluded that poorly controlled DM was correlated with poorer OS, PCSM, and PSA-RFS in locally advanced prostate cancer patients.

DeepFusion: A deep learning based multi-scale feature fusion method for predicting drug-target interactions.

Predicting drug-target interactions (DTIs) is essential for both drug discovery and drug repositioning. Recently, deep learning methods have achieved relatively significant performance in predicting DTIs. Generally, it needs a large amount of approved data of DTIs to train the model, which is actually tedious to obtain. In this work, we propose DeepFusion, a deep learning based multi-scale feature fusion method for predicting DTIs. To be specific, we generate global structural similarity feature based on similarity theory, convolutional neural network and generate local chemical sub-structure semantic feature using transformer network respectively for both drug and protein. Data experiments are conducted on four sub-datasets of BIOSNAP, which are 100%, 70%, 50% and 30% of BIOSNAP dataset. Particularly, using 70% sub-dataset, DeepFusion achieves ROC-AUC and PR-AUC by 0.877 and 0.888, which is close to the performance of some baseline methods trained by the whole dataset. In case study, DeepFusion achieves promising prediction results on predicting potential DTIs in case study.

Repair of complex digital soft-tissue defects using a free composite ulnar artery perforator flap from the volar wrist.

Digital skin defects resulting from trauma are often associated with dysfunction of the digital nerve and the extensor and flexor tendons in the affected fingers. The repair of these complex tissue defects requires a graft containing multiple tissues that can be used to reconstruct the tendons and nerves and restore the skin. Such procedures can cause multiple injuries and significant damage to the donor site. The current study used a novel technique to repair complex dorsal and palmar digital soft-tissue defects. First, multiple tissues were cut and collected from the donor site. Then, part of the flexor carpi ulnaris tendon was transplanted to repair the tendon defect, and a medial antebrachial cutaneous nerve graft was used to repair the digital nerve defect. Finally, a skin flap was used to cover the skin defect. This paper reports on 31 cases of complex soft-tissue digital defects, with defect areas of 2-18 cm2 . One patient presented with a postoperative arterial crisis in the flap. All other patients recovered without experiencing a vascular crisis, flap necrosis, or wound infection. The postoperative flaps were similar in texture to the original digital skin. The sensation and the extension/flexion functions in the affected fingers recovered well. The effect on grip strength, wrist flexion, and forearm sensation was minor and the postoperative total active motion scores of the affected digits were good or excellent in 96.77% of the cases. The flap sensation recovery rate was also excellent in 83.87% of the cases. The present technique facilitates the repair of multiple dorsal and palmar digital soft-tissue, tendon and nerve defects, reduces the damage to the donor site, and significantly improves the success of surgical repair.

Zinc Accumulation Aggravates Cerebral Ischemia/Reperfusion Injury Through Inducing Endoplasmic Reticulum Stress.

Zinc is highly enriched in the central nervous system. Numerous evidences suggest that high concentration of zinc acts as a critical mediator of neuronal death in the ischemic brain, however, the possible mechanisms of neurotoxicity of zinc during cerebral ischemia/reperfusion (I/R) remain elusive. Endoplasmic reticulum (ER) is a storage location of intracellular zinc. ER stress related genes were up-regulated during zinc-induced neuronal death in vascular-type senile dementia. In the present study, we investigated whether intracellular accumulated zinc aggravates I/R injury through ER stress and ER stress-associated apoptosis. Male Sprague-Dawley rats were subjected to 90 min middle cerebral artery occlusion (MCAO) and received either vehicle or zinc chelator TPEN 15 mg/kg. The expression of ER stress related factors glucose-regulated protein 78 (GRP78) and phosphorylated eukaryotic initiation factor 2α (p-eIF2α), ER stress related apoptotic proteins CCAAT-enhancer-binding protein homologous protein (CHOP) and caspase-12, as well as anti-apoptotic factor B-cell lymphoma-2 (Bcl-2) were assessed 24 h after reperfusion. Our results showed that the levels of GRP78 and p-eIF2α, as well as CHOP and caspase-12, were increased in ischemic brain, indicating that cerebral I/R triggers ER stress. Furthermore, GRP78, CHOP and caspase-12 were all colocalized with the zinc-specific dyes NG, suggesting that there is certain relationship between cytosolic labile zinc and ER stress following cerebral ischemia. Chelating zinc with TPEN reversed the expression of GRP78, p-eIF2α in ischemic rats. Moreover, CHOP and NeuN double staining positive cells, as well as caspase-12 and TUNEL double staining positive cells were also decreased after TPEN treatment, indicating that chelating zinc might inhibit ER stress and decreased ER stress associated neuronal apoptosis. In addition, TPEN treatment reversed the downregulated level of Bcl-2, which localized in the ER membrane and involved in the dysfunction of ER, confirming that the anti-apoptosis effects of chelating zinc following I/R are exerted via inhibition of the ER stress. Taken together, this study demonstrated that excessive zinc activates ER stress and zinc induced neuronal cell death is at least partially due to ER stress specific neuronal apoptosis in ischemic penumbra, which may provide an important mechanism of cerebral I/R injury.

Influence of Rosaceous Species and Driving Factors on Differentiation of Rhizospheric Bacteria in a Deciduous Broad-Leaved Forest.

Understanding plant-microbe interactions could provide the basis for improved phytoremediation, microbial resource utilization, and secondary metabolite production. Rhizosphere bacterial communities are strongly influenced by abiotic factors such as soil nutrient availability and the composition of such communities exhibits differentiation under different host plants. In a deciduous broad-leaved forest in Anhui Province, eastern China, the rhizospheric bacteria of three different tree species of the Rosaceae family (Sorbus alnifolia, Cerasus serrulata, and Photinia beauverdiana) were studied, with the bacteria of the bulk soil as controls. Bacterial community composition was determined using the Illumina platform for high-throughput sequencing of 16S rRNA genes. The results showed that the bacterial community composition varied between rhizospheric and bulk soils, and dominant bacterial phyla as Proteobacteria, Actinobacteria, and Acidobacteria were found in both soils. Information on predicted functional genes and pathways revealed significant differences between rhizospheric and bulk soil bacteria. It provided ample evidence for the different metabolic characteristics of the rhizosphere bacterial communities of the three tree species. Electrical conductivity (22.72%), total phosphorus concentration (21.89%), and urease activity (22%) were the main drivers for changes in the composition of the rhizosphere bacterial communities from the three tree species.

Primary hyperoxaluria diagnosed after kidney transplantation: a case report and literature review.

BACKGROUND: Primary hyperoxaluria (PH) is a rare inherited autosomal recessive disease caused by disturbed glyoxylate metabolism. The disease is characterized by calcium oxalate crystal deposition in various organs, especially in the kidney. Due to the lack of current understanding of PH, nearly all patients are only initially diagnosed with PH when recurrent lithiasis and progressive end-stage renal disease occur. Many cases are not diagnosed in patients until renal allograft insufficiency occurs after renal transplantation. This case report and literature review aim to emphasize the need for careful pre-transplant PH screening of patients with bilateral nephrocalcinosis or nephrolithiasis. CASE PRESENTATION: Renal allograft insufficiency was diagnosed as PH after kidney transplantation. Here, we detail the complete clinical course, including computed tomography images of the original kidney and renal graft, histopathological images of a biopsy of the transplanted kidney, the results of laboratory and molecular genetic tests, and the treatment. In addition, we reviewed the literature from 2000 to 2021 and analyzed 19 reported cases of PH diagnosed after kidney transplantation, and provide a summary of the characteristics, complications, treatment, and prognosis of these cases. CONCLUSIONS: By reviewing and analyzing these cases, we concluded that patients with a history of nephrocalcinosis or nephrolithiasis in both kidneys need preoperative screening for PH and appropriate treatment before kidney transplantation. Delayed graft function caused by PH is easily misdiagnosed as acute rejection, and needle biopsy should be performed at an early stage.

Lightweight Splint Design for Individualized Treatment of Distal Radius Fracture.

A systematic design approach is proposed for medical splints for individualized treatment of the distal radius fracture. An initial split structural model is first constructed by 3D scanning of an injured limb. Based on the biomechanical theory and clinical experiences, the topology optimization method is applied to design the splint structure. The optimized lightweight splint is realized by additive manufacturing using polylactic acid. Compared to the traditional designs for the distal radius fracture, the optimized design by the proposed approach exhibits a weight reduction of more than 40%. Besides, the mechanical properties of the splint meet the requirements of medical treatment according to the simulation results. Numerical examples are provided to demonstrate the applicability of the approach.

Exosomes Isolated From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by excessive accumulation of the amyloid-ß peptide (Aß) in the brain, which has been considered to mediate the neuroinflammation process. Microglial activation is the main component of neuroimmunoregulation. In recent years, exosomes isolated from human umbilical cord mesenchymal stem cells (hucMSC-exosomes) have been demonstrated to mimic the therapeutic effects of hucMSCs in many inflammation-related diseases. In this study, exosomes from the supernatant of hucMSCs were injected into AD mouse models. We observed that hucMSC-exosomes injection could repair cognitive disfunctions and help to clear Aß deposition in these mice. Moreover, we found that hucMSC-exosomes injection could modulate the activation of microglia in brains of the mice to alleviated neuroinflammation. The levels of pro-inflammatory cytokines in peripheral blood and brains of mice were increased and the levels of anti-inflammatory cytokines were decreased. We also treated BV2 cells with hucMSC-exosomes in culture medium. HucMSC-exosomes also had inflammatory regulating effects to alternatively activate microglia and modulate the levels of inflammatory cytokines in vitro.

Anti-tumor activity of phenoxybenzamine hydrochloride on malignant glioma cells.

Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function of PHEN in glioma. Cell proliferation assay was used to assess glioma cell growth. Migration and invasion capacity of glioma cells was monitored by wound-healing and transwell assay, respectively. Neurosphere formation test was adopted for the tumorigenesis of glioma cells, which was also confirmed by soft agar cloning formation test in vitro and a nude mouse model in vivo. Finally, we explored the potential pathway utilized by PHEN using Western blot and immunofluoresce staining. PHEN exhibited a significant inhibitory effect on the proliferation of both U251 and U87MG glioma cell lines in a positive dose-dependent manner. PHEN apparently attenuated the malignancy of glioma in terms of migration and invasion and also suppressed the tumorigenic capacity both in vitro and in vivo. Mechanism study showed that PHEN promoted tumor suppression by inhibiting the TrkB-Akt pathway. The results of the present study demonstrated that PHEN suppressed the proliferation, migration, invasion, and tumorigenesis of glioma cells, induced LINGO-1 expression, and inhibited the TrkB-Akt pathway, which may prove to be the mechanisms underlying the anti-tumor effect of PHEN on glioma cells.

[Phloroglucinol combined with parecoxib for cystospasm after transurethral resection of the prostate].

Objective: To evaluate the effect and safety of phloroglucinol combined with parecoxib on cystospasm after transurethral resection of the prostate (TURP). METHODS: We conducted a prospective randomized case-control study on 98 patients treated by TURP. After operation, the patients were randomly assigned to a treatment (n=50) and a control group (n=48), the former treated by intravenous injection of 80 mg phloroglucinol qd plus 40 mg parecoxib bid while the latter given 80 mg phloroglucinol only, both for 3 successive days. Then we recorded the frequency and duration of cystospasm, visual analogue scales (VAS), adverse reactions, post-operative bladder irrigation time, catheter-indwelling time, and hospital stay and compared them between the two groups of patients. RESULTS: Compared with the controls, the patients in the treatment group showed a significantly lower frequency of cystospasm (ï¼»1.95±0.14ï¼½ vs ï¼»0.70±0.65ï¼½ times, P<0.01), duration of cystospasm (ï¼»0.44±0.21ï¼½ vs ï¼»0.12±0.14ï¼½ min, P<0.01), and VAS score (2.70±1.80 vs 1.90±1.30, P<0.01) at 48－72 hours after TURP, but no statistically significant differences were found between the control and treatment groups in the post-operative bladder irrigation time (ï¼»2.75±0.87ï¼½ vs ï¼»2.64±0.83ï¼½ d, P>0.05), catheter-indwelling time (ï¼»3.52±0.32ï¼½ vs ï¼»3.44±0.42ï¼½ d, P>0.05), and hospital stay (ï¼»5.23±0.81ï¼½ vs ï¼»5.10±0.73ï¼½ d, P>0.05), and no obvious adverse reactions were observed in either of the two groups. CONCLUSIONS: Phloroglucinol combined with parecoxib is more effective and safer than phloroglucinol alone in relieving postoperative cystospasm after TURP.

[Safety and effectiveness of GreenLight 120-W laser photoselective vaporization of the prostate for benign prostatic hyperplasia: A meta-analysis].

OBJECTIVE: To evaluate the safety and effectiveness of GreenLight 120-W laser photoselective vaporization of the prostate (PVP) versus transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH). METHODS: We searched PubMed, Medline, Embase, Cochrane Library, Wanfang, CNKI, and VIP for randomized control trials and their references addressing 120-W PVP versus TURP in the treatment of BPH. Based on the inclusion and exclusion criteria, two reviewers independently accomplished the screening, quality assessment, and data extraction of the identified studies and performed meta-analyses using RevMan 5.2. RESULTS: Totally, 6 randomized control trials were included in this analysis, involving 703 cases, 351 treated by PVP and 352 by TURP. Compared with TURP, PVP showed significantly decreased time of catheterization (by 32. 55 hours, 95% CI 15.3 -49.8, P < 0.01), hospital stay (by 1.85 days, 95% CI 1.2-2.5, P < 0.01), and intraoperative blood loss (by 15.6 g/L, 95% CI 10.0-21.2, P < 0.01), but increased time of operation (by 9.37 minutes, 95% CI 5. 1-13.6, P < 0.01). There was also a significant reduction in blood transfusion, TUR syndrome, and capsular perforation in the PVP group. At 12 months after surgery, no statistically significant differences were found between the two groups in the improvement of maximum urinary flow rate, IPSS, postvoid residual, and sexual function. CONCLUSION: GreenLight 120-W laser PVP is a safe and effective procedure for the treatment of BPH, with similar effectiveness to TURP but less blood loss, shorter time of catheterization and hospital stay, and lower incidences of blood transfusion, TUR syndrome and capsular perforation.

Biomarker conversion from primary breast cancer to synchronous axillary lymph node metastasis and neoadjuvant therapy response: a single-center analysis.

PURPOSE: The biomarker characteristics of breast cancer plays an important role in predicting treatment sensitivity. The aim of the present study was to compare immunohistochemical profiles (ER, PR, HER2, and Ki67) between the primary tumor and synchronous axillary lymph node metastasis and investigate the subsequent effects on neoadjuvant therapy response. METHODS: A total of 358 patients with pathologically confirmed synchronous axillary lymph node metastasis at first diagnosis and treated by neoadjuvant therapy at Peking University First Hospital from January 1, 2013 to December 31, 2022 were included in this retrospective study. Clinicopathologic data, especially receptor status in primary and metastatic foci, was collected for each case. RESULTS: Change of ER, PR, HER2, and Ki67 expression was observed in 5.9%, 8.7%, 12.6%, and 17.3% of patients, respectively. HR discordance was observed more frequently when the ER status (p = 0.023) or PR status (p = 0.010) of primary tumor was negative, while HER2 discordance seemed to be more frequent when the HER2 status of primary tumor was HER2-0 or HER2-low (p < 0.001). Patients with loss of HR-positivity (positive to negative) responded to neoadjuvant chemotherapy better compared to those with stable positive HR expression (50% vs. 11.1%, p = 0.0017). A significantly decrease in pCR rate was observed in patients with unstable HER2 status, but not in the HER2-0/HER2-low subgroup. CONCLUSION: Receptor discordance between primary tumor and synchronous axillary LNM appears to already exist before any anti-tumor therapy. This instability has limited clinical impact on the choice of neoadjuvant therapy at current stage, but further investigation is warranted with the incremental application of endocrine drugs and ADCs in neoadjuvant therapy.

Sex-Specific Early Retinal Dysfunction in Mutant TDP-43 Transgenic Mice.

BACKGROUND: Increasing evidence has highlighted retinal impairments in neurodegenerative diseases. Dominant mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the accumulation of TDP-43 in the cytoplasm is a pathological hallmark of ALS, frontotemporal dementia (FTD), and many other neurodegenerative diseases. OBJECTIVE: While homozygous transgenic mice expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) experience premature death, hemizygous TDP-43M337V mice do not suffer sudden death, but they exhibit age-dependent motor-coordinative and cognitive deficits. This study aims to leverage the hemizygous TDP-43M337V mice as a valuable ALS/FTD disease model for the assessment also of retinal changes during the disease progression. METHODS: We evaluated the retinal function of young TDP-43M337V mice by full field electroretinogram (ERG) recordings. RESULTS: At 3-4 months of age, well before the onset of brain dysfunction at 8 months, the ERG responses were notably impaired in the retinas of young female TDP-43M337V mice in contrast to their male counterparts and age-matched non-transgenic mice. Mitochondria have been implicated as critical targets of TDP-43. Further investigation revealed that significant changes in the key regulators of mitochondrial dynamics and bioenergetics were only observed in the retinas of young female TDP-43M337V mice, while these alterations were not present in the brains of either gender. CONCLUSIONS: Together our findings suggest a sex-specific vulnerability within the retina in the early disease stage, and highlight the importance of retinal changes and mitochondrial markers as potential early diagnostic indicators for ALS, FTD, and other TDP-43 related neurodegenerative conditions.

Contribution of zinc accumulation to ischemic brain injury and its mechanisms about oxidative stress, inflammation, and autophagy: an update.

Ischemic stroke is a leading cause of death and disability worldwide, and presently, there is no effective neuroprotective therapy. Zinc is an essential trace element that plays important physiological roles in the central nervous system. Free zinc concentration is tightly regulated by zinc-related proteins in the brain under normal conditions. Disruption of zinc homeostasis, however, has been found to play an important role in the mechanism of brain injury following ischemic stroke. A large of free zinc releases from storage sites after cerebral ischemia, which affects the functions and survival of nerve cells, including neurons, astrocytes, and microglia, resulting in cell death. Ischemia-triggered intracellular zinc accumulation also disrupts the function of blood-brain barrier via increasing its permeability, impairing endothelial cell function, and altering tight junction levels. Oxidative stress and neuroinflammation have been reported to be as major pathological mechanisms in cerebral ischemia/reperfusion injury. Studies have showed that the accumulation of intracellular free zinc could impair mitochondrial function to result in oxidative stress, and form a positive feedback loop between zinc accumulation and reactive oxygen species production, which leads to a series of harmful reactions. Meanwhile, elevated intracellular zinc leads to neuroinflammation. Recent studies also showed that autophagy is one of the important mechanisms of zinc toxicity after ischemic injury. Interrupting the accumulation of zinc will reduce cerebral ischemia injury and improve neurological outcomes. This review summarizes the role of zinc toxicity in cellular and tissue damage following cerebral ischemia, focusing on the mechanisms about oxidative stress, inflammation, and autophagy.

Comparison of adverse effects of anti-tumor therapy for breast cancer shortly after COVID-19 diagnosis vs. the control period.

Background: COVID-19 is an acute infectious disease caused by SARS-CoV-2. The best time to restart antitumor therapy in breast cancer patients after SARS-CoV-2 infection is unknown. This study aimed to evaluate treatment-related adverse events in breast cancer patients who received antitumor therapies within a short time after SARS-CoV-2 infection (observation) as well as before (control) and to provide safety data. Methods: We conducted a self-controlled cohort study using the data from the Breast Disease Center of Peking University First Hospital. We identified patients who received antitumor therapy within 28 days after COVID-19 infection between December 20, 2022, and January 20, 2023. The primary outcome was treatment-related adverse events. McNemar's test was used to compare the incidence rate of adverse reactions between periods. Results: We identified 183 patients with breast cancer, of whom 109 were infected with SARS-CoV-2 within 28 days before antitumor treatment and were included. In total, 28 patients (25.7%) received neoadjuvant therapy, 60 (55.0%) received adjuvant therapy, and 21 (19.3%) received advanced rescue therapy. None of patients required hospitalization for severe or critical COVID-19, but 15 patients (13.8%) still had sequelae of COVID-19 while receiving antitumor treatment. The most common adverse events were peripheral neuropathy (n = 32 [29.4%]), pain (n = 29 [26.6%]), fatigue (n = 28 [25.7%]), nausea (n = 23 [21.1%]), and neutropenia (n = 19 [17.4%]). There was no increased risk of overall treatment-related adverse events (n = 87 [79.8%] vs. n = 91 [83.5%]; p = 0.42) or serious adverse events (n = 13 [11.9%] vs. n = 12 [11.0%]; p = 1.00) from receiving antitumor therapy shortly after the diagnosis of COVID-19. We also found no increased risk in subgroup analyses, and no patients discontinued antitumor therapy due to adverse events. Conclusion: Restarting antitumor therapy 2-4 weeks after having mild or moderate COVID-19 is a relatively safe strategy for breast cancer patients that does not increase the risk of treatment-related adverse events.

Zinc accumulation aggravates cerebral ischemia/reperfusion injury by promoting inflammation.

Intracellular zinc accumulation has been shown to be associated with neuronal death after cerebral ischemia. However, the mechanism of zinc accumulation leading to neuronal death in ischemia/reperfusion (I/R) is still unclear. Intracellular zinc signals are required for the production of proinflammatory cytokines. The present study investigated whether intracellular accumulated zinc aggravates I/R injury through inflammatory response, and inflammation-mediated neuronal apoptosis. Male Sprague-Dawley rats were treated with vehicle or zinc chelator TPEN 15 mg/kg before a 90-min middle cerebral artery occlusion (MCAO). The expressions of proinflammatory cytokines TNF-α, IL-6, NF-κB p65, and NF-κB inhibitory protein IκB-α, as well as anti-inflammatory cytokine IL-10 were assessed at 6 or 24 h after reperfusion. Our results demonstrated that the expression of TNF-α, IL-6, and NF-κB p65 increased after reperfusion, while the expression of IκB-α and IL-10 decreased, suggesting that cerebral ischemia triggers inflammatory response. Furthermore, TNF-α, NF-κB p65, and IL-10 were all colocalized with the neuron-specific nuclear protein (NeuN), suggesting that the ischemia-induced inflammatory response occurs in neurons. Moreover, TNF-α was also colocalized with the zinc-specific dyes Newport Green (NG), suggesting that intracellular accumulated zinc might be associated with neuronal inflammation following cerebral I/R. Chelating zinc with TPEN reversed the expression of TNF-α, NF-κB p65, IκB-α, IL-6, and IL-10 in ischemic rats. Besides, IL-6-positive cells were colocalized with TUNEL-positive cells in the ischemic penumbra of MCAO rats at 24 h after reperfusion, indicating that zinc accumulation following I/R might induce inflammation and inflammation-associated neuronal apoptosis. Taken together, this study demonstrates that excessive zinc activates inflammation and that the brain injury caused by zinc accumulation is at least partially due to specific neuronal apoptosis induced by inflammation, which may provide an important mechanism of cerebral I/R injury.

Nitric oxide promotes cerebral ischemia/reperfusion injury through upregulating hypoxia-inducible factor1-α-associated inflammation and apoptosis in rats.

Nitric oxide (NO) was one of the key factors to sustain hypoxia-inducible factor-1- α (HIF-1α) activation during hypoxia. However, the mechanism by which NO production promotes upregulation of HIF-1α to cause cerebral ischemia/reperfusion (I/R) injury remains unclear. The present study investigated whether eliminating NO would decrease HIF-1α level, and then reduce the subsequent inflammatory actions as well as neuronal apoptotic death in middle cerebral artery occlusion (MCAO) rats. Our results revealed that HIF-1α was correlated with 3-NT, a marker for nitrosative/oxidative stress, in the brain of MCAO rats. Treatment with NOS inhibitor L-NAME suppressed HIF-1α/3-NT double-positive cells, suggesting that HIF-1α was correlated with NO overproduction during cerebral I/R. Furthermore, pro-inflammatory cytokines TNF-α, IL-1ß and NF-κB p65 were significantly increased and colocalized with HIF-1α in the brain of MCAO rats, all of which could be attenuated by NO inhibition, suggesting that eliminating NO reduced MCAO-induced HIF-1α upregulation, which in turn exerted anti-inflammatory actions. Accordingly, cleaved caspase-3, as well as HIF-1α and TUNEL double-positive cells in ischemic brain were also decreased by L-NAME treatment. These results suggest that NO accumulation after cerebral ischemia leads to HIF-1α upregulation, which may activate pro-inflammatory cytokines, resulting in neuronal apoptotic death. These findings demonstrate a novel mechanism of NO-induced cerebral I/R injury.