A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429), which was originally detected in California, carries spike glycoprotein mutations S13I in the signal peptide, W152C in the N-terminal ...domain (NTD), and L452R in the receptor-binding domain (RBD). Plasma from individuals vaccinated with a Wuhan-1 isolate-based messenger RNA vaccine or from convalescent individuals exhibited neutralizing titers that were reduced 2- to 3.5-fold against the B.1.427/B.1.429 variant relative to wild-type pseudoviruses. The L452R mutation reduced neutralizing activity in 14 of 34 RBD-specific monoclonal antibodies (mAbs). The S13I and W152C mutations resulted in total loss of neutralization for 10 of 10 NTD-specific mAbs because the NTD antigenic supersite was remodeled by a shift of the signal peptide cleavage site and the formation of a new disulfide bond, as revealed by mass spectrometry and structural studies.
Congenital mesenteric defect is a rare cause of neonatal small bowel obstruction. We present a case of a newborn with cystic fibrosis experiencing small bowel herniation through a congenital ...mesenteric defect leading to bowel ischemia.
A 0-day-old term, 3.2 kg female with a family history of cystic fibrosis carrier was evaluated for abdominal distension. Prenatal ultrasound showed bowel dilation with increased wall thickness, and post-delivery abdominal X-ray showed a cystic dilation of the bowel. Contrast fluoroscopy of the lower gastrointestinal tract showed small intestinal filling defects and microcolon. She was treated for suspected meconium ileus. Bowel dilation progressed necessitating exploratory laparotomy on day of life 4, with findings of jejunal perforation and ischemic ileal dilatation secondary to herniation through a congenital mesenteric defect. Ileal resection and ileal-ileal anastomosis with jejunostomy creation were performed. The postoperative course of ostomy takedown was complicated by anastomotic breakdown, requiring ileostomy creation. Genetic testing revealed cystic fibrosis. Because of high ileostomy output and meconium impaction in the distal bowel, Bishop-Koop ostomy construction and ileocolic anastomosis were performed. The residual small intestine was 61 cm with an ileocecal valve. At age 2, she remained dependent on total parental nutrition and gastrostomy tube feeding, with intestinal failure and chronic liver failure.
Herniation through a congenital mesenteric defect is an extremely rare differential diagnosis for neonatal bowel obstruction. Concomitant cystic fibrosis can compromise postoperative management and cause complications resulting in short gut syndrome due to multiple surgical interventions.
level 5.
Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to ...guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma samples from 130 hemodialysis and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naïve hemodialysis patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity. Patients followed up to 7 months after vaccination showed a rapid decay of the antibody response with an average 21- and 10-fold reduction of neutralizing antibodies to vaccine-matched SARS-CoV-2 and Delta variant, which increased the fraction of non-responders to 84% and 90%, respectively. These data indicate that dialysis patients should be prioritized for additional vaccination boosts. Nevertheless, their antibody response to SARS-CoV-2 must be continuously monitored to adopt the best prophylactic and therapeutic strategy.
Abstract
Background
In addition to the well-known role of vitamin D in calcium homeostasis and bone metabolism, vitamin D is important in the modulation of the immune system and inflammatory ...processes. Vitamin D deficiency is common in patients with systemic lupus erythematosus (SLE), possibly as a result of sun avoidance. The aim of this prospective open-label study was to assess the effect of the treatment of vitamin D deficiency and insufficiency in SLE patients, particularly with regards to disease activity, fatigue and interferon signature gene expression.
Methods
31 SLE patients, 13 with vitamin D deficiency and 18 with vitamin D insufficiency were treated with vitamin D3. They were supplemented with vitamin D3 8000 IU daily for 8 weeks if they were vitamin D deficient, or 8000 IU daily for 4 weeks if they were insufficient. This was followed by 2000 IU daily maintenance. They were assessed at baseline, after 6 and 12 months by means of an interview, filling in questionnaires and blood tests. The expression of 12 interferon signature genes in RNA extracted from whole blood was measured by using QuantiGene Plex technology.
Results
An improvement in disease activity measured by systemic lupus erythematosus disease activity index-2K (SLEDAI-2K;
p
= 0.028) and fatigue measured by fatigue severity scale (FSS;
p
= 0.071) at 12 months were noted. A significant decrease in anti-double stranded deoxyribonucleic acid (dsDNA) titre (
p
= 0.045) was also noted. The mean interferon signature gene expression score decreased from baseline to 6 months, however statistical significance was not achieved (
p
= 0.165).
Conclusions
Improved disease activity and fatigue have been noted when Vitamin D has been supplemented in vitamin D deficient/insufficient SLE patients. One possible mechanism could be the suppression of the interferon signature gene expression.
Trial registration
: The study was registered with the ISRCTN registry on 12/04/2021 (Trial ID: ISRCTN59058825).
The complexity of the phosphatase, PP2A, is being unravelled and current research is increasingly providing information on the association of deregulated PP2A function with cancer initiation and ...progression. It has been reported that decreased activity of PP2A is a recurrent observation in many types of cancer, including colorectal and breast cancer (Baldacchino et al. EPMA J. 5:3,
2014
; Cristobal et al. Mol Cancer Ther. 13:938–947,
2014
). Since deregulation of PP2A and its regulatory subunits is a common event in cancer, PP2A is a potential target for therapy (Baldacchino et al. EPMA J. 5:3,
2014
). In this review, the structural components of the PP2A complex are described, giving an in depth overview of the diversity of regulatory subunits. Regulation of the active PP2A trimeric complex, through phosphorylation and methylation, can be targeted using known compounds, to reactivate the complex. The endogenous inhibitors of the PP2A complex are highly deregulated in cancer, representing cases that are eligible to PP2A-activating drugs. Pharmacological opportunities to target low PP2A activity are available and preclinical data support the efficacy of these drugs, but clinical trials are lacking. We highlight the importance of PP2A deregulation in cancer and the current trends in targeting the phosphatase.
The Hippo kinase cascade, a growth‐suppressive pathway that ultimately antagonizes the transcriptional coactivator Yes‐associated protein (YAP), has been shown in transgenic animals to orchestrate ...organ size regulation. The purpose of this study was to determine whether in non–genetically modified mice (1) the Hippo pathway is involved in the regulation of adaptive liver enlargement caused by the mitogen 1,4‐bis2‐(3,5‐dichloropyridyloxy)benzene (TCPOBOP), an agonist of constitutive androstane receptor and (2) a dysregulation of this pathway occurs during the development of chemically induced hepatocellular carcinoma (HCC). We show that liver enlargement caused by TCPOBOP was associated with an increase of YAP protein levels that paralleled the increase in 2‐bromodeoxyuridine incorporation. Interestingly, when a second dose of TCPOBOP was given to mice with enlarged livers, no further increases in liver mass or YAP protein levels were observed, suggesting that the Hippo pathway prevents further growth of the hyperplastic liver. Viral‐mediated exogenous expression of active YAP in mouse livers was able to partially overcome the block of hepatocyte proliferation. We also show that HCCs developed in mice given diethylnitrosamine and then subjected to repeated treatments with TCPOBOP had increased levels of YAP that were associated with down‐regulation of microRNA 375, which is known to control YAP expression, and with enhanced levels of alpha‐fetoprotein and connective tissue growth factor, two target genes of YAP.
Conclusion:
These results suggest that the Hippo pathway regulates adaptive liver enlargement and is probably inactivated in initiated cells that escape the suppressive constrain exerted on the surrounding normal tissue, thus allowing clonal expansion to HCC (HEPATOLOGY 2011;)
Gastric prolapse through a gastrostomy site is a rare but potentially fatal complication in gastrostomy-tube (G-tube) dependent pediatric patients. We describe a case of strangulated gastric prolapse ...through a gastrostomy site in a 5-month-old patient with chronic respiratory failure, poor nutritional status, and multiple preceding G-tube complications. The patient required immediate surgical evaluation and underwent operative reduction and gastrostomy access revision within hours of presentation. There are documented cases of gastric prolapse in pediatric and adult patients, but there is no standardized management strategy. In this paper, we aim to increase vigilance of gastric prolapse in high-risk pediatric patients and to demonstrate a management plan that focuses on rapid surgical assessment and intervention to prevent significant morbidity and mortality.
Appendicitis in the infant population is rare and often misdiagnosed. It can be associated with perforation and sepsis and necessitates expedient identification when present in a sick infant. We ...describe a case of perforated appendicitis in a 10-month-old infant after diagnostic workup ruled out common causes of colicky abdominal pain. We highlight documented recommendations for workup and management of neonatal and infantile appendicitis. We show that the consensus in literature is prompt diagnosis and surgical intervention for the best chance at preventing morbid outcomes that increase mortality.
Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity, and cross-reactivity of serum antibodies and MBCs in 155 ...SARS-CoV-2 infected and vaccinated individuals over a 16-month time frame. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both prefusion and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sublineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants.
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•SARS-CoV-2 infection and vaccines induce specific memory B cells that reach steady-state levels•mRNA COVID-19 vaccines elicit prefusion Spike-specific memory B cell responses•Postfusion Spike-specific memory B cells cross-react with human betacoronaviruses•Antibody avidity rises over time raising resilience to escape by variants of concern
Immunology; Virology
CIP2A is emerging as an oncoprotein overexpressed commonly across many tumours and generally correlated with higher tumour grade and therapeutic resistance. CIP2A drives an oncogenic potential ...through inhibiting protein phosphatase 2A, stabilizing MYC, and promoting epithelial-to-mesenchymal transition, although further biological mechanisms for CIP2A are yet to be defined. CIP2A protein expression was studied by immunohistochemistry in oestrogen receptor–positive primary breast cancers (n = 250) obtained from the Leeds Tissue Bank. In total, 51 cases presented with a relapse or metastasis during adjuvant treatment with tamoxifen and were regarded as tamoxifen resistant. CIP2A expression was scored separately for cytoplasmic, nuclear, or membranous staining, and scores were tested for statistically significant relationships with clinicopathological features. Membranous CIP2A was preferentially expressed in cases who experienced a recurrence during tamoxifen treatment thus predicting a worse overall survival (log rank = 8.357, p = 0.004) and disease-free survival (log rank = 21.766, p < 0.001). Cox multivariate analysis indicates that it is an independent prognostic indicator for overall survival (hazard ratio = 4.310, p = 0.013) and disease-free survival (hazard ratio = 5.449, p = 0.002). In this study, we propose the assessment of membranous CIP2A expression as a potential novel prognostic and predictive indicator for tamoxifen resistance and recurrence within oestrogen receptor–positive breast cancer.
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