Therapy-induced senescent cancer cells exhibit complement activation and increased complement regulatory protein expression.

Therapy-induced senescence (TIS) is a primary response to chemotherapy, contributing to untoward treatment outcomes such as evasion of immunosurveillance. Despite the established role of the complement system in the immune response to cancer, the role of complement in mediating the immune response against senescent tumor cells remains poorly understood. To explore this relationship, we exposed lung adenocarcinoma (A549), breast adenocarcinoma (MCF7) and pancreatic carcinoma (Panc-1) cell lines to sublethal doses of either etoposide or doxorubicin to trigger TIS. Identification of TIS was based on morphological changes, upregulation of the senescence-associated ß-galactosidase, p21Cip1 induction and lamin B1 downregulation. Using immunofluorescence microscopy, quantitative PCR, ELISA of conditioned media and in silico analysis, we investigated complement activation, complement protein expression, C3 levels in the conditioned media of senescent cells and secreted complement proteins as part of the senescence-associated secretory phenotype (SASP), respectively. In cell lines undergoing TIS, complement-related changes included (i) activation of the terminal pathway, evidenced by the deposition of C5b-9 on senescent cells; (ii) an increase in the expression of CD59 and complement factor H and (iii) in A549 cells, an elevation in the expression of C3 with its secretion into the medium. In addition, increased C3 expression was observed in breast cancer samples expressing TIS hallmarks following exposure to neoadjuvant chemotherapy. In conclusion, TIS led to the activation of complement, upregulation of complement regulatory proteins and increased C3 expression. Complement appears to play a role in shaping the cancer microenvironment upon senescence induction.

The efficacy of Linum usitatissimum seeds to inhibit estrogen receptor as a natural therapy for PCOS: An in silico and in vitro analysis.

Polycystic ovarian syndrome (PCOS) is an endocrinological disorder aroused due to hormonal disturbances. It is characterized by anovulation due to an excess of androgen and estrogen hormones, thus leading to the formation of multiple cysts, imposing life-threatening conditions. This manuscript aimed to introduce a natural estrogen receptor (ESR) inhibitors that can provide protection against PCOS. The computational analysis of Linum usitatissimum seeds  compounds against ESR alpha receptor was performed, and the binding affinities of the ligand compounds and receptor proteins were scrutinized. Nine lignin compounds were docked, and the results were compared with that of reference estrogen receptor inhibitors, clomiphene, and tamoxifen. The binding affinity scores for pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol were -10.67, -10.66, -10.91, and -10.60 kcal mol-1 , respectively. These were comparable to the binding affinity score of reference compounds -11.406 kcal mol-1 for clomiphene and -10.666 kcal mol-1 for tamoxifen. Prime MM-GBSA studies showcased that Linum usitatissimum seeds compounds exhibit significant efficacy and efficiency towards receptor protein. Moreover, MD-simulation studies were performed and the results depict that the lignin compounds form stable complexes at 300 K throughout the simulation time. For further clarity, in-vitro experiments were carried out. The results exhibit the decline in cell proliferation in a concentration-dependent manner by extract 1 (ethyl acetate) EX1 and extract 2 (petroleum ether) EX2. Hence, providing evidence regarding the anti-estrogenic activity of the sample extracts. Collectively, these results showed that flax seed can reduce the levels of estrogen, which can induce ovulation and prevent cyst formation, and ultimately can provide protection against PCOS.

Clinical outcomes of percutaneous coronary intervention for chronic total occlusion by treated segment length.

BACKGROUND: Long lesions are known to have worse outcomes following percutaneous coronary intervention (PCI), but there are limited data assessing the association between lesion length and clinical outcomes in PCI procedures undertaken in chronic total occlusions (CTO). METHODS AND RESULTS: We formed a longitudinal cohort (2006-2018, n = 27,205) of stable angina patients who underwent PCI to CTO in the British Cardiovascular Intervention Society (BCIS) database. Clinical, demographical, procedural, and outcome data were analyzed in three groups by treated segment length, < 30 mm (n = 11,782), 30-59 mm (n = 10,415), ≥ 60 mm (n = 5008). Prevalence of previous myocardial infarction and PCI were higher in patients in 30-59 mm group or ≥ 60 mm group compared with < 30 mm group. Following multivariable analysis, no significant difference was observed in in-patient death (OR = 30-59 mm group = 1.10, CI:0.55-2.19, p = 0.78) (OR ≥ 60 mm group = 0.82, CI: 0.33-2.05, p = 0.67), and 1-year death (OR = 30-59 mm group = 1.06, CI: 0.81-1.37, p = 0.69) (OR ≥ 60 mm group =1.01, CI: 0.70-1.43, p = 0.99) (< 30 mm group = reference) but in-patient MACE was higher in > = 60 mm group (OR: 1.52, CI: 1.15-2.01, p = 0.06) but similar in 30-59 mm group (OR: 1.16, CI: 0.91-1.48, p = 0.22) compared with < 30 mm group. The adjusted rates of procedural complications were higher in ≥ 60 mm group (OR: 1.61, CI: 1.40-1.85, p < 0.001) but were similar in 30-59 mm group (OR: 1.06, CI: 0.94-1.20, p < 0.31) compared with < 30 mm group. For every 10 mm increase, there was an increased adjusted risk of in-patient procedural complications and coronary perforation but not in-patient MACE or death. CONCLUSION: Patients with very long CTO lesions have higher risk of procedural complications and in-patient MACE but similar risk of short or long-term mortality compared with short CTO lesions.

Diagnostic accuracy of computer aided reading of chest x-ray in screening for pulmonary tuberculosis in comparison with Gene-Xpert.

BACKGROUND & OBJECTIVES: Pakistan ranked fifth amongst 22 high-burden Tuberculosis countries, and it is an epidemic in Pakistan, hence screening is performed nationally, as part of the ambitious ZERO TB drive. Our objective was to assess the diagnostic accuracy of Computer Aided Detection (CAD4TB) software on chest Xray in screening for pulmonary tuberculosis in comparison with gene-Xpert. METHODS: The study was conducted by Radiology Department Lady Reading Hospital Peshawar in affiliation with Indus Hospital network over a period of one year. Screening was done by using mobile Xray unit equipped with CAD4TB software with scoring system. All of those having score of more than 70 and few selected cases with strong clinical suspicion but score of less than 70 were referred to dedicated TB clinic for Gene-Xpert analysis. RESULTS: Among 26,997 individuals screened, 2617 (9.7%) individuals were found presumptive for pulmonary TB. Sputum samples for Gene-Xpert were obtained in 2100 (80.24%) individuals, out of which 1825 (86.9%) were presumptive for pulmonary TB on CAD4TB only. Gene-Xpert was positive in 159 (8.7%) patients and negative in 1,666(91.3%). Sensitivity and specificity of CAD4TB and symptomatology with threshold score of ≥70 was 83.2% and 12.7% respectively keeping Gene-Xpert as gold standard. CONCLUSION: Combination of chest X-ray analysis by CAD4TB and symptomatology is of immense value to screen a large population at risk in a developing high burden country. It is significantly a more effective tool for screening and early diagnosis of TB in individuals, who would otherwise go undiagnosed.

Radiographic patterns on Chest X-ray as a supporting imaging tool in triaging of suspected Corona Virus Disease (COVID) patients.

Objective: To evaluate the radiographic patterns on Chest X-Ray (CXR) in accordance with Modified Brixia Scoring as supporting imaging tool in triaging of Corona Virus Disease (COVID-19) pneumonia. Methods: In this cross-sectional study, chest radiographs of suspected COVID patients at emergency triage, Lady Reading Hospital (LRH) from April 18th to July 22nd 2020 were evaluated for patterns of COVID pneumonia and scored in accordance with modified Brixia score. Each zone was categorized as score of "one" for interstitial pattern, "two" for mixed interstitial /alveolar pattern and "three" for alveolar pattern. Radiographic patterns consistent with COVID pneumonia or patients having strong clinical suspicion were advised Polymerase Chain Reaction (PCR) tests. Results: Total of 2,225 individuals were screened for patterns of COVID-19 pneumonia on chest radiograph. Out of these 1465(65.8%) had normal chest radiograph and 760(34.2%) had abnormal findings. Out of the total, 648 suspected COVID patients were selected for PCR. The radiographic patterns ranged from mixed interstitial/alveolar pattern in 261(40.3%) patients, alveolar pattern in 231(35.6%), interstitial pattern in 87(13.4%), pleural effusion in 12(1.9%), other findings in 5(0.8%) while 52(8%) suspected Covid patients had normal radiographs. The PCR was positive in 326(50.3%), negative in 100(15.4%) and inconclusive in 60(9.3%) while 162(25%) were lost to follow up. Amongst the 52 suspected Covid patients having normal chest radiographs, 10 were positive on PCR, 21 negative, seven suspected and two inconclusive, while 12 were lost to follow up. Conclusion: Chest radiograph is used for triaging of suspected COVID pneumonia patients in emergency settings. It assesses the severity of disease according to modified Brixia scoring for treatment plan.

The Systemin Signaling Cascade As Derived from Time Course Analyses of the Systemin-responsive Phosphoproteome.

Systemin is a small peptide with important functions in plant wound response signaling. Although the transcriptional responses of systemin action are well described, the signaling cascades involved in systemin perception and signal transduction at the protein level are poorly understood. Here we used a tomato cell suspension culture system to profile phosphoproteomic responses induced by systemin and its inactive Thr17Ala analog, allowing us to reconstruct a systemin-specific kinase/phosphatase signaling network. Our time-course analysis revealed early phosphorylation events at the plasma membrane, such as dephosphorylation of H+-ATPase, rapid phosphorylation of NADPH-oxidase and Ca2+-ATPase. Later responses involved transient phosphorylation of small GTPases, vesicle trafficking proteins and transcription factors. Based on a correlation analysis of systemin-induced phosphorylation profiles, we predicted substrate candidates for 44 early systemin-responsive kinases, which includes receptor kinases and downstream kinases such as MAP kinases, as well as nine phosphatases. We propose a regulatory module in which H+-ATPase LHA1 is rapidly de-phosphorylated at its C-terminal regulatory residue T955 by phosphatase PLL5, resulting in the alkalization of the growth medium within 2 mins of systemin treatment. We found the MAP kinase MPK2 to have increased phosphorylation level at its activating TEY-motif at 15 min post-treatment. The predicted interaction of MPK2 with LHA1 was confirmed by in vitro kinase assays, suggesting that the H+-ATPase LHA1 is re-activated by MPK2 later in the systemin response. Our data set provides a resource of proteomic events involved in systemin signaling that will be valuable for further in-depth functional studies in elucidation of systemin signaling cascades.

Maternal Instruction About Jaundice and the Incidence of Acute Bilirubin Encephalopathy in Nigeria.

OBJECTIVE: To evaluate whether teaching mothers about neonatal jaundice will decrease the incidence of acute bilirubin encephalopathy among infants admitted for jaundice. STUDY DESIGN: This was a multicenter, before-after and cross-sectional study. Baseline incidences of encephalopathy were obtained at 4 collaborating medical centers between January 2014 and May 2015 (Phase 1). Structured jaundice instruction was then offered (May to November 2015; Phase 2) in antenatal clinics and postpartum. Descriptive statistics and logistic regression models compared 3 groups: 843 Phase 1 controls, 338 Phase 2 infants whose mothers received both antenatal and postnatal instruction (group A), and 215 Phase 2 infants whose mothers received no instruction (group B) either because the program was not offered to them or by choice. RESULTS: Acute bilirubin encephalopathy occurred in 147 of 843 (17%) Phase 1 and 85 of 659 (13%) Phase 2 admissions, which included 63 of 215 (29%) group B and 5 of 338 (1.5%) group A infants. OR for having acute bilirubin encephalopathy, comparing group A and group B infants adjusted for confounding risk factors, was 0.12 (95% CI 0.03-0.60). Delayed care-seeking (defined as an admission total bilirubin ≥18 mg/dL at age ≥48 hours) was the strongest single predictor of acute bilirubin encephalopathy (OR 11.4; 6.6-19.5). Instruction decreased delay from 49% to 17%. Other major risk factors were home births (OR 2.67; 1.69-4.22) and hemolytic disease (hematocrit ≤35% plus bilirubin ≥20 mg/dL) (OR 3.03; 1.77-5.18). The greater rate of acute bilirubin encephalopathy with home vs hospital birth disappeared if mothers received jaundice instruction. CONCLUSIONS: Providing information about jaundice to mothers was associated with a reduction in the incidence of bilirubin encephalopathy per hospital admission.

Protease activated receptor 2 (PAR2) activation causes migraine-like pain behaviors in mice.

BACKGROUND: Pain is the most debilitating symptom of migraine. The cause of migraine pain likely requires activation of meningeal nociceptors. Mast cell degranulation, with subsequent meningeal nociceptor activation, has been implicated in migraine pathophysiology. Degranulating mast cells release serine proteases that can cleave and activate protease activated receptors. The purpose of these studies was to investigate whether protease activated receptor 2 is a potential generator of nociceptive input from the meninges by using selective pharmacological agents and knockout mice. METHODS: Ratiometric Ca++ imaging was performed on primary trigeminal and dural cell cultures after application of 2at-LIGRL-NH2, a specific protease activated receptor 2 agonist. Cutaneous hypersensitivity and facial grimace was measured in wild-type and protease activated receptor 2-/- mice after dural application of 2at-LIGRL-NH2 or compound 48-80, a mast cell degranulator. Behavioral experiments were also conducted in mice after dural application of 2at-LIGRL-NH2 (2AT) in the presence of either C391, a selective protease activated receptor 2 antagonist, or sumatriptan. RESULTS: 2at-LIGRL-NH2 evoked Ca2+ signaling in mouse trigeminal neurons, dural fibroblasts and in meningeal afferents. Dural application of 2at-LIGRL-NH2 or 48-80 caused dose-dependent grimace behavior and mechanical allodynia that were attenuated by either local or systemic application of C391 as well as in protease activated receptor 2-/- mice. Nociceptive behavior after dural injection of 2at-LIGRL-NH2 was also attenuated by sumatriptan. CONCLUSIONS: Functional protease activated receptor 2 receptors are expressed on both dural afferents and fibroblasts and activation of dural protease activated receptor 2 produces migraine-like behavioral responses. Protease activated receptor 2 may link resident immune cells to meningeal nociceptor activation, driving migraine-like pain and implicating protease activated receptor 2 as a therapeutic target for migraine in humans.

Neural Mechanisms Responsible for Vagus Nerve Stimulation-Dependent Enhancement of Somatosensory Recovery.

Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. To do so, we characterized the effect of tactile rehabilitation combined with VNS across a range of stimulation intensities on recovery of somatosensory function in a rat model of chronic sensory loss in the forelimb. Consistent with previous studies in other applications, we find that moderate intensity VNS yields the most effective restoration of somatosensation, and both lower and higher VNS intensities fail to enhance recovery compared to rehabilitation without VNS. We next used the optimized intensity to evaluate the mechanisms that underlie recovery. We find that moderate intensity VNS enhances transcription of Arc, a canonical mediator of synaptic plasticity, in the cortex, and that transcript levels were correlated with the degree of somatosensory recovery. Moreover, we observe that blocking plasticity by depleting acetylcholine in the cortex prevents the VNS-dependent enhancement of somatosensory recovery. Collectively, these findings identify neural mechanisms that subserve VNS-dependent somatosensation recovery and provide a basis for selecting optimal stimulation parameters in order to facilitate translation of this potential intervention.

The Era of Precision Nutrition in the Field of Reproductive Health and Pregnancy.

When it comes to reproductive health, various lifestyle habits can act as major contributors to either an optimized or worsened scenario of female and male fertility [...].

Gut microbiome and Parkinson's disease: Perspective on pathogenesis and treatment.

BACKGROUND: Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain. AIM: of Review: In this review, we summarize how alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved inneuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further exploredin humans through clinical trials. Key Scientific Concepts of Review: Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.

A Guide to Flow Cytometry: Components, Basic Principles, Experimental Design, and Cancer Research Applications.

Flow cytometry (FCM) is a state-of-the-art technique for the qualitative and quantitative assessment of cells and other particles' physical and biological properties. These cells are suspended within a high-velocity fluid stream and pass through a laser beam in single file. The main principle of the FCM instrument is the light scattering and fluorescence emission upon the interaction of the fluorescent particle with the laser beam. It also allows for the physical sorting of particles depending on different parameters. A flow cytometer comprises different components, including fluidic, optics, and electronics systems. This article briefly explains the mechanism of all components of a flow cytometer to clarify the FCM technique's general principles, provides some useful guidelines for the proper design of FCM panels, and highlights some general applications and important applications in cancer research. © 2023 Wiley Periodicals LLC.

A Systematic Review and Meta-Analysis of Independent Predictors for Acute Respiratory Distress Syndrome in Patients Presenting With Sepsis.

The current meta-analysis was conducted to determine the predictors of acute respiratory distress syndrome (ARDS) in patients with sepsis. The present meta-analysis was conducted in accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. We conducted a systematic search using the PubMed, Cochrane Library, and EMBASE databases for studies published between 1 January 2000 and 28 February 2023 that assessed the predictors of ARDS in patients with sepsis. We used key terms such as "predictors," "acute respiratory distress syndrome," and "sepsis" to search for relevant articles. Our search was limited to human studies published in English. A total of six studies were included in this meta-analysis. Of the six studies, four were retrospective and two were prospective. The pooled incidence of ARDS was 11.27%. We identified six factors with a consistent and statistically significant association with ARDS, including sequential organ failure assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE) II score, pulmonary sepsis, smoking, pancreatitis, and C-reactive protein. Age, diabetes, and chronic obstructive pulmonary disease (COPD) were not found to be significantly associated with ARDS in this patient population. It is important for healthcare providers to consider these predictors when assessing patients with sepsis and septic shock to identify those at high risk for developing ARDS and implement appropriate preventive measures.

Investigating the Utility of the SOFA Score and Creating a Modified SOFA Score for Predicting Mortality in the Intensive Care Units in a Tertiary Hospital in Jordan.

Background: The utility of the Sequential Organ Failure Assessment (SOFA) score in predicting mortality in the intensive care unit (ICU) has been demonstrated before, but serial testing in various settings is required to validate and improve the score. This study examined the utility of the SOFA score in predicting mortality in Jordanian ICU patients and aimed to find a modified score that required fewer laboratory tests. Methods: A prospective observational study was conducted at Jordan University Hospital (JUH). All adult patients admitted to JUH ICUs between June and December 2020 were included in the study. SOFA scores were measured daily during the whole ICU stay. A modified SOFA score (mSOFA) was constructed from the available laboratory, clinical, and demographic data. The performance of the SOFA, mSOFA, qSOFA, and SIRS in predicting ICU mortality was assessed using the area under the receiver operating characteristic curve (AUROC). Results: 194 patients were followed up. SOFA score (mean ± SD) at admission was significantly higher in non-survivors (7.5 ± 3.9) compared to survivors (2.4 ± 2.2) and performed the best in predicting ICU mortality (AUROC = 0.8756, 95% CI: 0.8117-0.9395) compared to qSOFA (AUROC = 0.746, 95% CI: 0.655-0.836) and SIRS (AUROC = 0.533, 95% CI: 0.425-0.641). The constructed mSOFA included points for the hepatic and CNS SOFA scores, in addition to one point each for the presence of chronic kidney disease or the use of breathing support; it performed as well as the SOFA score in this cohort or better than the SOFA score in a subgroup of patients with heart disease. Conclusion: SOFA score was a good predictor of mortality in a Jordanian ICU population and better than qSOFA, while SIRS could not predict mortality. Furthermore, the proposed mSOFA score which employed fewer laboratory tests could be used after validation from larger studies.

Effective Delivery of Vagus Nerve Stimulation Requires Many Stimulations Per Session and Many Sessions Per Week Over Many Weeks to Improve Recovery of Somatosensation.

BACKGROUND: Chronic sensory loss is a common and undertreated consequence of many forms of neurological injury. Emerging evidence indicates that vagus nerve stimulation (VNS) delivered during tactile rehabilitation promotes recovery of somatosensation. OBJECTIVE: Here, we characterize the amount, intensity, frequency, and duration of VNS therapy paradigms to determine the optimal dosage for VNS-dependent enhancement of recovery in a model of peripheral nerve injury (PNI). METHODS: Rats underwent transection of the medial and ulnar nerves in the forelimb, resulting in chronic sensory loss in the paw. Eight weeks after injury, rats were implanted with a VNS cuff and received tactile rehabilitation sessions consisting of repeated mechanical stimulation of the previously denervated forepaw paired with short bursts of VNS. Rats received VNS therapy in 1 of 6 systematically varied dosing schedules to identify a paradigm that balanced therapy effectiveness with a shorter regimen. RESULTS: Delivering 200 VNS pairings a day 4 days a week for 4 weeks produced the greatest percent improvement in somatosensory function compared to any of the 6 other groups (One Way analysis of variance at the end of therapy, F[4 70] P = .005). CONCLUSIONS: Our findings demonstrate that an effective VNS therapy dosage delivers many stimulations per session, with many sessions per week, over many weeks. These results provide a framework to inform the development of VNS-based therapies for sensory restoration.

High fat diet exacerbates long-term metabolic, neuropathological, and behavioral derangements in an experimental mouse model of traumatic brain injury.

AIMS: Traumatic brain injury (TBI) constitutes a serious public health concern. Although TBI targets the brain, it can exert several systemic effects which can worsen the complications observed in TBI subjects. Currently, there is no FDA-approved therapy available for its treatment. Thus, there has been an increasing need to understand other factors that could modulate TBI outcomes. Among the factors involved are diet and lifestyle. High-fat diets (HFD), rich in saturated fat, have been associated with adverse effects on brain health. MAIN METHODS: To study this phenomenon, an experimental mouse model of open head injury, induced by the controlled cortical impact was used along with high-fat feeding to evaluate the impact of HFD on brain injury outcomes. Mice were fed HFD for a period of two months where several neurological, behavioral, and molecular outcomes were assessed to investigate the impact on chronic consequences of the injury 30 days post-TBI. KEY FINDINGS: Two months of HFD feeding, together with TBI, led to a notable metabolic, neurological, and behavioral impairment. HFD was associated with increased blood glucose and fat-to-lean ratio. Spatial learning and memory, as well as motor coordination, were all significantly impaired. Notably, HFD aggravated neuroinflammation, oxidative stress, and neurodegeneration. Also, cell proliferation post-TBI was repressed by HFD, which was accompanied by an increased lesion volume. SIGNIFICANCE: Our research indicated that chronic HFD feeding can worsen functional outcomes, predispose to neurodegeneration, and decrease brain recovery post-TBI. This sheds light on the clinical impact of HFD on TBI pathophysiology and rehabilitation as well.

Vagus Nerve Stimulation Must Occur During Tactile Rehabilitation to Enhance Somatosensory Recovery.

Chronic sensory loss is a common and undertreated consequence of many forms of neurological injury. Emerging evidence indicates that vagus nerve stimulation (VNS) delivered during tactile rehabilitation promotes recovery of somatosensation. Here, we systematically varied the timing of VNS relative to tactile rehabilitation to determine the paradigm that yields the greatest degree of somatosensory recovery after peripheral nerve injury (PNI). The medial and ulnar nerves in rats were transected, causing chronic sensory loss. Eight weeks after injury, rats were given a VNS implant followed by four weeks of tactile rehabilitation sessions consisting of repeated mechanical stimuli to the previously denervated forepaw. Rats received VNS before, during, or after tactile rehabilitation. Delivery of VNS during rehabilitative training generates robust, significant recovery compared to rehabilitative training without stimulation (56 ± 14% improvement over sham stimulation). A matched amount of VNS before training, immediately after training, or two hours after training is significantly less effective than VNS during rehabilitative training and fails to improve recovery compared to rehabilitative training alone (5 ± 10%, 4 ± 11%, and -7 ± 22% improvement over sham stimulation, respectively). These findings indicate that concurrent delivery of VNS during rehabilitative training is most effective and illustrate the importance of considering stimulation timing for clinical implementation of VNS therapy.

The Emerging Role of the Gut Microbiome in the Cancer Response to Immune Checkpoint Inhibitors: A Narrative Review.

The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the care of cancer patients. However, the response to ICI therapy exhibits substantial interindividual variability. Efforts have been directed to identify biomarkers that predict the clinical response to ICIs. In recent years, the gut microbiome has emerged as a critical player that influences the efficacy of immunotherapy. An increasing number of studies have suggested that the baseline composition of a patient's gut microbiota and its dysbiosis are correlated with the outcome of cancer immunotherapy. This review tackles the rapidly growing body of evidence evaluating the relationship between the gut microbiome and the response to ICI therapy. Additionally, this review highlights the impact of antibiotic-induced dysbiosis on ICI efficacy and discusses the possible therapeutic interventions to optimize the gut microbiota composition to augment immunotherapy efficacy.

Anti-SARS-Cov-2 S-RBD IgG Formed after BNT162b2 Vaccination Can Bind C1q and Activate Complement.

Background: The ability of vaccine-induced antibodies to bind C1q could affect pathogen neutralization. In this study, we investigated C1q binding and subsequent complement activation by anti-spike (S) protein receptor-binding domain (RBD) specific antibodies produced following vaccination with either the mRNA vaccine BNT162b2 or the inactivated vaccine BBIBP-CorV. Methods: Serum samples were collected in the period of July 2021-March 2022. Participants' demographic data, type of vaccine, date of vaccination, as well as adverse effects of the vaccine were recorded. The serum samples were incubated with S protein RBD-coated plates. Levels of human IgG, IgA, IgM, C1q, and mannose-binding lectin (MBL) that were bound to the plate, as well as formed C3d, and C5b-9 were compared between different groups of participants. Results: A total of 151 samples were collected from vaccinated (n = 116) and nonvaccinated (n = 35) participants. Participants who received either one or two doses of BNT162b2 formed higher levels of anti-RBD IgG and IgA than participants who received BBIBP-CorV. The anti-RBD IgG formed following either vaccine bound C1q, but significantly more C1q binding was observed in participants who received BNT162b2. Subsequently, C5b-9 formation was significantly higher in participants who received BNT162b2, while no significant difference in C5b-9 formation was found between the nonvaccinated and BBIBP-CorV groups. The formation of C5b-9 was strongly correlated to C1q binding and not to MBL binding, additionally, the ratio of formed C5b-9/bound C1q was significantly higher in the BNT162b2 group. Conclusion: Anti-RBD IgG formed following vaccination can bind C1q with subsequent complement activation, and the degree of terminal complement pathway activation differed between vaccines, which could play a role in the protection offered by COVID-19 vaccines. Further investigation into the correlation between vaccine protection and vaccine-induced antibodies' ability to activate complement is required.

Complement Terminal Pathway Activation is Associated with Organ Failure in Sepsis Patients.

BACKGROUND: Complement plays a pivotal role in the immune response to infection. Several studies demonstrated complement activation in sepsis, yet little is known of the relationship of complement terminal pathway activation and the clinical characteristics of sepsis patients. Therefore, we investigated serum C5, soluble C5b-9 (sC5b-9), and soluble CD59 (sCD59) and their relation to organ failure in sepsis patients in the intensive care unit (ICU). METHODS: In this prospective cohort study, all available patients admitted to the adult ICUs between June 2020 and January 2021 were included. Patients were divided into sepsis and non-sepsis groups according to the Sepsis-3 criteria, serum samples from both groups were investigated for the levels of C5, sC5b-9, and sCD59 using commercial sandwich ELISA kits. RESULTS: We analyzed 79 serum samples, 36 were from sepsis patients. We found that sepsis patients had significantly lower C5 (83.6± 28.4 vs 104.4± 32.0 µg/mL, p = 0.004) and higher sCD59 (380.7± 170.5 vs 288.9± 92.5 ng/mL, p = 0.016). sC5b-9, although higher in sepsis patients, did not reach statistical significance (1.5± 0.8 µg/mL vs 1.3± 0.7 µg/mL, p = 0.293). Sepsis patients who died during their ICU stay had significantly higher sCD59 compared to those who survived (437.0 ± 176.7 vs 267.8 ± 79.7 ng/mL, p = 0.003, respectively). Additionally, C5 and sCD59 both correlated to SOFA score in the sepsis group (rs = -0.44, P = 0.007 and = 0.43, P = 0.009, respectively), and a similar correlation was not found in the non-sepsis group. DISCUSSION: In sepsis patients, levels of C5 and sCD59, but not sC5b-9, correlated to the severity of organ damage measured by SOFA. A similar correlation was not found in non-sepsis patients. This indicated that organ damage associated with sepsis led to a more pronounced terminal pathway activation than in non-sepsis patients, it also indicated the potential of using C5 and sCD59 to reflect sepsis severity.