Natural Parasite Exposure Induces Protective Human Anti-Malarial Antibodies.

Antibodies against the NANP repeat of circumsporozoite protein (CSP), the major surface antigen of Plasmodium falciparum (Pf) sporozoites, can protect from malaria in animal models but protective humoral immunity is difficult to induce in humans. Here we cloned and characterized rare affinity-matured human NANP-reactive memory B cell antibodies elicited by natural Pf exposure that potently inhibited parasite transmission and development in vivo. We unveiled the molecular details of antibody binding to two distinct protective epitopes within the NANP repeat. NANP repeat recognition was largely mediated by germline encoded and immunoglobulin (Ig) heavy-chain complementarity determining region 3 (HCDR3) residues, whereas affinity maturation contributed predominantly to stabilizing the antigen-binding site conformation. Combined, our findings illustrate the power of exploring human anti-CSP antibody responses to develop tools for malaria control in the mammalian and the mosquito vector and provide a molecular basis for the structure-based design of next-generation CSP malaria vaccines.

Rescue of cone and rod photoreceptor function in a CDHR1-model of age-related retinal degeneration.

Age-related macular degeneration (AMD) is the most common cause of untreatable blindness in the developed world. Recently, CDHR1 has been identified as the cause of a subset of AMD that has the appearance of the "dry" form, or geographic atrophy. Biallelic variants in CDHR1-a specialized protocadherin highly expressed in cone and rod photoreceptors-result in blindness from shortened photoreceptor outer segments and progressive photoreceptor cell death. Here we demonstrate long-term morphological, ultrastructural, functional, and behavioral rescue following CDHR1 gene therapy in a relevant murine model, sustained to 23-months after injection. This represents the first demonstration of rescue of a monogenic cadherinopathy in vivo. Moreover, the durability of CDHR1 gene therapy seems to be near complete-with morphological findings of the rescued retina not obviously different from wildtype throughout the lifespan of the mouse model. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted. Hypomorphic CDHR1 variants may mimic advanced dry AMD. Accurate clinical classification is now critical, as their pathogenesis and treatment are distinct.

Postoperative pancreatic fistula after pancreaticogastrostomy versus pancreatojejunostomy after pancreatic resection, a comparative systematic review and meta-analysis.

BACKGROUND: In patients undergoing pancreaticoduodenectomy (PD), there has been some evidence favoring pancreaticogastrostomy (PG) over pancreatojejunostomy (PJ) in the occurrence of postoperative pancreatic fistulas (POPF) and considering PG as a safer anastomotic technique. However, other publications revealed comparable incidences of POPF attributed to both techniques. The current work attempts to reach a more consolidated conclusion about such an issue. METHODS: This is a systematic review and meta-analysis that analyzed the studies comparing PG and PJ during PD in terms of the rate of POPF occurrence. Studies were obtained by searching the Scopus, PubMed Central, and Cochrane Central Register of Controlled Trials databases. RESULTS: 35 articles published between 1995 and 2022 presented data from 14,666 patients; 4547 underwent PG and 10,119 underwent PJ. Statistically significant lower rates of POPF (p = 0.044) and clinically relevant CR-POPF (p = 0.043) were shown in the PG group. The post-pancreatectomy hemorrhage (PPH) was significantly higher in the PG group, while no significant difference was found between the two groups in the clinically significant PPH. No statistically significant differences were found regarding the amount of intraoperative blood loss, length of hospital stay, DGE, overall morbidity rates, reoperation rates, or mortality rates. The percentage of male sex in the PG group and the percentage of soft pancreas in the PJ group seem to influence the odds ratio of CR-POPF (p = 0.076 and 0.074, respectively). CONCLUSION: The present study emphasizes the superiority of PG over PJ regarding CR-POPF rates. Higher rates of postoperative hemorrhage were associated with PG. Yet, the clinically significant hemorrhage rate was comparable between the two groups.

Outcomes of revisional surgery options after inadequate sleeve gastrectomy: A comprehensive network meta-analysis.

BACKGROUND: Despite the success of sleeve gastrectomy (SG) in of weight loss and treatment of the medical problems associated with obesity, some concerns have arisen about the need for revisional surgeries after SG in some patients. This study aimed to present an updated and comprehensive comparison among the presently available revisional surgeries employed explicitly in cases of inadequate outcomes after SG, which is the most frequently performed bariatric surgery in contemporary practice. METHODS: This network meta-analysis included studies that compared the outcomes of different revisional bariatric procedures after an inadequate outcome of SG. RESULTS: Searching across the electronic databases yielded 31 eligible articles. Re-SG was associated with the highest rate of significant complications. Patients treated with single anastomosis duodenal-ileal bypass (SADI) had a significantly higher percentage of total weight loss (%TWL) than those treated with one anastomosis gastric bypass (OAGB) and Roux-en-Y gastric bypass (RYGB). The percentage of excess weight loss (%EWL) at the end of the follow-up period was significantly higher in patients in the SADI group compared to those in the RYGB group and the OAGB, and re-SG exhibited the least values compared to SADI, biliopancreatic diversion with duodenal switch (BPD/DS), and OAGB. Significantly lower rates of reflux worsening/de novo development were observed in the SADI group compared to the OAGB group and the re-SG group, which showed significantly higher rates than SADI and RYGB. CONCLUSION: Our comprehensive network meta-analysis highlights SADI as a promising revisional option post-SG, demonstrating superior weight loss outcomes, lower significant complication rates, and a favorable impact on reflux compared to other procedures. While acknowledging the limitations of our study, these findings support the potential efficacy of SADI in addressing the challenges of inadequate weight loss after sleeve gastrectomy.

CRISPR Manipulation of Age-Related Macular Degeneration Haplotypes in the Complement System: Potential Future Therapeutic Applications/Avenues.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among the elderly in the developed world. Whilst AMD is a multifactorial disease, the involvement of the complement system in its pathology is well documented, with single-nucleotide polymorphisms (SNPs) in different complement genes representing an increased risk factor. With several complement inhibitors explored in clinical trials showing limited success, patients with AMD are still without a reliable treatment option. This indicates that there is still a gap of knowledge in the functional implications and manipulation of the complement system in AMD, hindering the progress towards translational treatments. Since the discovery of the CRISPR/Cas system and its development into a powerful genome engineering tool, the field of molecular biology has been revolutionised. Genetic variants in the complement system have long been associated with an increased risk of AMD, and a variety of haplotypes have been identified to be predisposing/protective, with variation in complement genes believed to be the trigger for dysregulation of the cascade leading to inflammation. AMD-haplotypes (SNPs) alter specific aspects of the activation and regulation of the complement cascade, providing valuable insights into the pathogenic mechanisms of AMD with important diagnostic and therapeutic implications. The effect of targeting these AMD-related SNPs on the regulation of the complement cascade has been poorly explored, and the CRISPR/Cas system provides an ideal tool with which to explore this avenue. Current research concentrates on the association events of specific AMD-related SNPs in complement genes without looking into the effect of targeting these SNPs and therefore influencing the complement system in AMD pathogenesis. This review will explore the current understanding of manipulating the complement system in AMD pathogenesis utilising the genomic manipulation powers of the CRISPR/Cas systems. A number of AMD-related SNPs in different complement factor genes will be explored, with a particular emphasis on factor H (CFH), factor B (CFB), and complement C3 (C3).

Factors affecting symptom duration and recovery among home-treated COVID- 19 patients in Baghdad-Iraq: a cross-sectional study.

OBJECTIVE: To determine the prevalence of Long COVID among home-treated coronavirus disease-2019 cases, and the factors that may influence the duration of symptoms. METHODS: The cross-sectional study was conducted from February to July 2021 at 20 primary healthcare centres in 10 health districts of Baghdad, Iraq, after approval from the ethics review committee of the College of Medicine, Mustansiriyah University, Baghdad. Those included were adults of both genders who previously had coronavirus disease-2019 infection as diagnosed through on polymerase chain reaction test, and received supportive treatment during isolation at home. Data was collected through direct interview using a questionnaire which consisted of demographic characteristics, comorbidities, smoking history and symptoms of coronavirus disease-2019 along with their duration. Measurement of weight and height was also done for each subject. Data was analysed using SPSS 27. RESULTS: Of the 400 participants, 248(62%) were males and 152(38%) were females. The overall mean age was 40.8±12.8 years (range: 18-71 years). Of the total, 121(30.25%) subjects had persistent symptoms for >4 weeks. The mean duration of illness was 4.2±3.6 weeks (range: 1-16 weeks). The symptoms that lasted for >4 weeks were fatigue 94(23.5%), loss of smell or taste 59(14.75%), and cough 8(2%). Age, smoking status, comorbidities and the total number of initial symptoms showed a significant association with the duration of illness (p<0.05). CONCLUSIONS: A substantial number of mild to moderate coronavirus disease-2019 cases suffered from persistent symptoms. The duration of illness could have been influenced by age, comorbidities, smoking status and total number of initial symptoms.

Enhanced Wound Healing Potential of Spirulina platensis Nanophytosomes: Metabolomic Profiling, Molecular Networking, and Modulation of HMGB-1 in an Excisional Wound Rat Model.

Excisional wounds are considered one of the most common physical injuries. This study aims to test the effect of a nanophytosomal formulation loaded with a dried hydroalcoholic extract of S. platensis on promoting excisional wound healing. The Spirulina platensis nanophytosomal formulation (SPNP) containing 100 mg PC and 50 mg CH exhibited optimum physicochemical characteristics regarding particle size (598.40 ± 9.68 nm), zeta potential (-19.8 ± 0.49 mV), entrapment efficiency (62.76 ± 1.75%), and Q6h (74.00 ± 1.90%). It was selected to prepare an HPMC gel (SPNP-gel). Through metabolomic profiling of the algal extract, thirteen compounds were identified. Molecular docking of the identified compounds on the active site of the HMGB-1 protein revealed that 12,13-DiHome had the highest docking score of -7.130 kcal/mol. SPNP-gel showed higher wound closure potential and enhanced histopathological alterations as compared to standard (MEBO® ointment) and S. platensis gel in wounded Sprague-Dawley rats. Collectively, NPS promoted the wound healing process by enhancing the autophagy process (LC3B/Beclin-1) and the NRF-2/HO-1antioxidant pathway and halting the inflammatory (TNF-, NF-κB, TlR-4 and VEGF), apoptotic processes (AIF, Caspase-3), and the downregulation of HGMB-1 protein expression. The present study's findings suggest that the topical application of SPNP-gel possesses a potential therapeutic effect in excisional wound healing, chiefly by downregulating HGMB-1 protein expression.

The neuroprotective effects of Piracetam on cisplatin-induced cognitive decline.

AIM: This work explores the effect of Cisplatin-a chemotherapeutic agent known to cause deterioration in cognitive function in cancer patients, and spatial memory in mice. It also investigates the potential neuroprotective effects of Piracetam, which is a nootropic drug recognized for improving cognitive ability. MATERIALS AND METHODS: The study incorporates four groups of mice receiving varied medication regimens, with memory tested using the Novel Location Recognition (NLR) method. RESULTS: The findings from our study revealed that memory decline and a suppression of cellular proliferation were observed in adult male mice subjected to Cisplatin treatment; furthermore, a decline in antioxidant efficacy within the hippocampal dentate gyrus was evident. Moreover, analysis of treatment effects on the animals' weight revealed that the Cisplatin and Piracetam group exhibited the most significant weight loss during drug administration. Despite the significant weight loss, the simultaneous use of Cisplatin and Piracetam demonstrated a notable improvement in memory and an augmentation of hippocampal proliferation and antioxidant effect. LIMITATIONS: It is important to note that our study was hampered by budget limits, a lack of additional animals, and mice's low tolerance for protracted treatment. CONCLUSIONS: Should the outcomes of Piracetam observed in this investigation be applicable to patients, it might offer a relatively straightforward approach to mitigate the cognitive impacts endured by cancer survivors following exposure to chemotherapy. Future research will be needed to study Piracetam's effect on mice with brain cancer after Cisplatin treatment in order to extrapolate the results onto cancer patients.

An investigation into managerial support for the psychological wellbeing of national health service doctors during the Covid-19 pandemic: A cross sectional study.

AIM: This study investigates the psychological wellbeing of United Kingdom National Health Service doctors during the Covid-19 pandemic and evaluates how they have been supported managerially. METHOD: A mixed-method sequential study design of online surveys and semi-structured interviews was employed between July-August 2020, with a response rate of 273/300 and 4/4 respectively. The Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) and Health and Safety Executive Management Standards (HSE MS) were used as measuring tools. The Jobs Demands Resource (JD-R) model and its relation to psychological wellbeing was determined. Survey findings informed semi-structured interviews, coded using thematic analysis. RESULTS: Overall mean WEMWBS, 43.2 (SD = 9.44), was low as was mean managerial support, 2.38 (SD = 0.78). Overall mean clinical demand score was high (2.6 on reverse scale). First year female trainee respondents from frontline specialties were found to have low psychological wellbeing scores. Key correlations were found between high managerial support, low clinical demands and low psychological wellbeing (r > 0.6). Core themes emerged: (1) breakdown of leadership, (2) vulnerability of wellbeing without support, (3) suboptimal navigation through change and (4) poor physical and human resource management. CONCLUSION: Maintaining the psychological wellbeing of doctors requires physical and psychological resources to meet clinical demands and the enhancement of fundamental managerial principles of control, communication, change management and leadership through adversity.

Out-of-plane beam shaping with UV-written tilted Bragg gratings for beam delivery on quantum chips.

We theoretically and numerically investigate the performance of tilted Bragg gratings in planar waveguides, fabricated by direct UV writing in photosensitive silica, to couple light out of a chip. An analytic expression is derived for the coupling efficiency and validated numerically by finite element simulations. Using the analytic result, we can design gratings to generate output beams in free space of any specific shape and calculate their overall power coupling efficiency. Our simulations indicate that for currently achievable grating index contrasts devices of millimeter length are most suitable for this technology.

Ursodeoxycholic acid for the prevention of gall stones after laparoscopic sleeve gastrectomy: a prospective controlled study.

BACKGROUND: Obesity is a risk factor for cholelithiasis. Besides, rapid weight loss after bariatric surgery upsurges the rate of cholelithiasis and acute cholecystitis. This study aimed to compare gallstone development frequency after LSG under ursodeoxycholic acid (UDCA) prophylaxis. METHODS: This prospective controlled study included 332 patients scheduled for LSG randomized to receive 500 mg UDCA daily for 12 months (UDCA Group) or no treatment (Control Group). Ultrasonography was done 6 and 12 months after surgery to detect gallstones. Cholecystectomy was done for complicated cases of cholelithiasis. RESULTS: Seventy-one patients were lost to follow-up, and 3 developed severe adverse effects of UDCA and excluded. Data are presented for 130 patients in the UDCA group and 128 in the Control group. Collectively, 11 patients (8.5%) of the UDCA group and 41 (32.0%) of the Control group developed gall stones during the first postoperative year (p < 0.001). Cholecystectomy was indicated in 3 patients (2.3%) of the UDCA group and 9 (7.0%) of the Control group (p = 0.072). On multivariate analysis, higher BMI, dyslipidemia, and lacking UDCA prophylaxis were the independent factors significantly associated with stone development. Also, stone development was associated with higher weight loss after 6 and 12 months. CONCLUSION: UDCA 500 mg once daily for 12 months after LSG is effective in reducing gallstone formation at 1 year. UDCA administration reduced the frequency of cholecystectomies from 7 to 2.3%. High BMI and dyslipidemia are the independent preoperative factors significantly associated with stone development.

Effect of preoperative diet regimen on liver size before laparoscopic sleeve gastrectomy in morbidly obese patients.

BACKGROUND: Low caloric diet can reduce liver volume; however, there is no consensus regarding preoperative weight reduction before bariatric surgery. This study evaluates the effect of preoperative very-lowcalorie diet (VLCD) in patients undergoing laparoscopic sleeve gastrectomy (LSG). METHODS: This prospective study included patients scheduled for LSG stratified into two groups, Diet Group (n = 183) who followed a preoperative VLCD regimen for three weeks and underwent assessment of the liver lobes span before and after regimen, and Control Group (n = 138) who underwent sonographic assessment once before surgery and were operated upon without diet. The outcome measures were the impact of preoperative diet on the liver span, intraoperative complications, anthropometric factors affecting the liver span. RESULTS: Diet regimen resulted in a significant reduction of the right and left lobes. The percentage of the reduction of the left lobe span was significantly higher than that of the right lobe (p < 0.001). Change of the size of the two lobes was correlated positively with weight and body mass index and initial size of both lobes. There was no significant difference between the two groups in the frequency of operative complications. CONCLUSION: VLCD for three weeks before bariatric surgery effectively reduced liver size. The reduction is more in the left lobe. The changes of both lobes were correlated well with the pre- and post-regimen weight and BMI. It was also positively correlated with the initial size of both lobes.

Effects of Gastric Bypass and Sleeve Gastrectomy on Bone Mineral Density and Bone Turnover Markers: A Systematic Review and Meta-Analysis.

BACKGROUND: There is a growing interest in the post-operative bone-related effects of bariatric surgery. However, little is known about the comparative effects of the most commonly performed bariatric procedures, namely Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). OBJECTIVES: To systematically assess the differences in areal bone mineral density (aBMD) and biochemical and hormonal markers of bone metabolism among patients undergoing RYGB and SG. METHODS: We conducted a systematic review and meta-analysis of studies aBMD at different sites, as well as bone-specific alkaline phosphatase (BALP), 25-OH-vitamin D, calcium and parathyroid hormone (PTH) after RYGB and SG. RESULTS: Fourteen studies were included (717 patients, 50.63% in the RYGB arm). Based on data collected at 1 year, 2 years and > 2 years, there were no significant differences in aBMD measurements at the total hip, lumbar spine, femoral neck, and the whole body with no statistical heterogeneity among different comparisons. Patients in the RYGB group showed significantly higher concentrations of BALP at 1 year (SMD = 0.52, 95%CI, 0.23-0.81, p = 0.0004) and PTH at > 2 years of follow-up (SMD = 0.68, 95%CI, 0.31-1.05, p = 0.0003) compared to the SG group. CONCLUSION: There were no significant differences in aBMD measurements at the hip, lumbar spine, femoral neck, and the total body following RYGB and SG procedures. However, BALP and PTH concentrations were significantly higher after RYGB surgeries compared to SG. Attention should be paid to patients undergoing RYGB to prevent the expected skeletal fragility over time.

An Electrostatic MEMS Roll-Pitch Rotation Rate Sensor with In-Plane Drive Mode.

In this paper, we presented a novel electrostatic Roll/Pitch MEMS gyroscope with in-plane drive mode and out-of-plane sense mode. The proposed structure is developed based on a tuning fork gyroscope with decoupled sense mass on each tine that control the sense out-of-plane frequency. A multi-height deep reactive ion etching (DRIE) fabrication process was utilized to achieve and enhance decoupling between the drive and sense modes. We presented our design methodology followed by an analytical and finite element (FEM) model. Our experimental results showed a good match between the analytical model and those obtained experimentally, from the drive and sense oscillation frequencies. Our characterization setup used a custom made application specific integrated circuit (ASIC) for characterization and was able to achieve ARW of 0.2 deg/rt-h, a bias instability 5.5 deg/h, and scale factor non-linearity (SFNL) 156 ppm FS.

Minicircle Delivery to the Neural Retina as a Gene Therapy Approach.

Non-viral gene therapy has the potential to overcome several shortcomings in viral vector-based therapeutics. Methods of in vivo plasmid delivery have developed over recent years to increase the efficiency of non-viral gene transfer, yet further improvements still need to be made to improve their translational capacity. Gene therapy advances for inherited retinal disease have been particularly prominent over the recent decade but overcoming physical and physiological barriers present in the eye remains a key obstacle in the field of non-viral ocular drug delivery. Minicircles are circular double-stranded DNA vectors that contain expression cassettes devoid of bacterial DNA, thereby limiting the risks of innate immune responses induced by such elements. To date, they have not been extensively used in pre-clinical studies yet remain a viable vector option for the treatment of inherited retinal disease. Here, we explore the potential of minicircle DNA delivery to the neural retina as a gene therapy approach. We consider the advantages of minicircles as gene therapy vectors as well as review the challenges involved in optimising their delivery to the neural retina.

Effect of laparoscopic sleeve gastrectomy on vasoactive mediators in obese hypertensive patients: A prospective study.

INTRODUCTION: The causal relationship between obesity and high blood pressure is established; however, the detailed pathways for such association are still under research. This work aims to assess the changes in neprilysin, vasoconstrictor and vasodilatory molecules in obese hypertensive patients undergoing laparoscopic sleeve gastrectomy (LSG). PATIENTS: The present prospective study was done on 59 hypertensive obese patients in whom LGS was performed. Blood pressure, as well as blood samples for neprilysin, angiotensinogen, angiotensin II, renin, endothelin-1 "ET-1", aldosterone, atrial natriuretic peptide "ANP" and B-type natriuretic peptide "BNP", were assessed before and 15 months after surgery. Patients were divided into two groups according to the remission of hypertension (HTN). RESULTS: After 15 months, remission of hypertension was seen in 42 patients (71%). The declines in the following measurements were significantly higher in patients with remission than those with persistent HTN: aldosterone (p = .029567), angiotensin II (p < .000001), angiotensinogen (p = .000021), neprilysin (p = .000601), renin (p = .000454) and endothelin-1(p = .000030). There was a significantly higher increment in ANP (p = .000002) and a non-significant increment in BNP (p = .081740). Angiotensin II 15 months after LSG and Δ ANP % were significant independent predictors of persistent HTN. CONCLUSION: In the setting of LSG, aldosterone, angiotensinogen, angiotensin II, renin and neprilysin were significantly lower in patients with remission of HTN after 15 months than those with persistent HTN, and natriuretic peptides were significantly higher. A lower postoperative level of angiotensin II and a larger percentage increment of ANP are independently associated with hypertension remission after LSG.

Distinct genetic landscape and a low response to doxorubicin in a luminal-A breast cancer cell line of Pakistani origin.

BACKGROUND: Breast cancers exhibit genetic heterogeneity which causes differential responses to various chemotherapy agents. Given the unique demographic and genomic background in South Asia, genetic architecture in breast cancers is not fully explored. METHODS AND RESULTS: In this study, we determined the genetic landscape of our previously established luminal-A subtype breast cancer cell line (BC-PAK1), and compared it with a Caucasian origin MCF7 breast cancer cell line of the same molecular subtype. Deep whole-exome sequencing (100X) was performed from early passages of the primary cancer cells using the Illumina NextSeq500. Data analysis with in silico tools showed novel non-silent somatic mutations previously not described in breast cancers, including a frameshift insertion (p.Ala1591AlafsTer28) in CIC, and a frameshift deletion (p.Lys333LysfsTer21) in PABPC1. Five genes CDC27, PIK3CG, ARAP3, RAPGEF1, and EFNA3, related with cell cycle pathway (hsa04110), ErbB signaling pathway (hsa04012), Ras signaling pathway (hsa04014), and Rap1 signaling pathway (hsa04015) were found to have recurrent non-silent somatic mutations. Further, the major contribution of COSMIC signatures 3 (failure of DNA double-strand break repair by homologous recombination), and 12 (transcriptional strand-bias for T>C substitutions) was observed. Also, the somatic mutations landscape in BC-PAK1 was found to be different as compared to the MCF7 cell line. The unique genetic landscape of BC-PAK1 might be responsible for significantly reduced response to doxorubicin than the MCF7 cell line. CONCLUSION: This study presents a distinct genetic architecture in luminal-A breast cancer potentially responsible for differential response to chemotherapy. Further studies on large cohorts of breast cancer patients are suggested for implementation in personalized medicine.

REV7 counteracts DNA double-strand break resection and affects PARP inhibition.

Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

Impact of laparoscopic sleeve gastrectomy on fibrosis stage in patients with child-A NASH-related cirrhosis.

PURPOSE: Bariatric surgery can improve non-alcoholic fatty liver disease (NAFLD). Yet data on the effect on fibrosis are insufficient and controversial. This work endeavored to evaluate the safety of laparoscopic sleeve gastrectomy (LSG) in cases that have compensated non-alcoholic steatohepatitis (NASH)-related cirrhosis and its impact on fibrosis stage. METHODS: The current prospective work involved 132 cases with Child-A NASH-related cirrhosis suffering from morbid obesity scheduled for LSG. They were subjected to preoperative assessment, wedge biopsy, and ultrasound-guided true-cut liver biopsy after 30 months. Patients were included if proved to have F4 fibrosis initially. The liver condition was assessed based on the NALFD Activity Score (NAS). The primary outcome measure was the impact of LSG on fibrosis stage and its relation to weight loss. RESULTS: The analysis included only 71 patients who completed the 30-month follow-up period. By the end of the follow-up interval, there was a substantial weight loss with a reasonable resolution of comorbidities. The median NAS decreased significantly from 6 (1-8) to 3 (0-6) after surgery. Fibrosis score regressed to F2 in 19 patients (26.8%) and F3 in 29 (40.8%). Patients with improved scores had a significantly higher amount of weight loss (p < 0.001). Improvement was more frequent in males (p = 0.007). By 30 months after treatment, 53.8% of cases with borderline NASH and 36.8% of those with probable NASH showed complete resolution, and 44.7% of patients with NASH showed improvement. Steatosis improved in 74.6% of patients (p < 0.001). CONCLUSION: In patients with NASH-related liver cirrhosis of Child class A, LSG may be a secure approach for the management of morbid obesity. It has a long-term benefit for both obesity and liver condition with significant improvement of steatosis, steatohepatitis, and fibrosis.

Long-term effects of one-anastomosis gastric bypass on liver histopathology in NAFLD cases: a prospective study.

PURPOSE: Weight reduction can effectively improve nonalcoholic fatty liver disease (NAFLD), which is a constant companion of severe obesity. This study aimed to determine the effect of one-anastomosis gastric bypass (OAGB) on pathological liver changes in severely obese cases with NAFLD. METHODS: The present prospective research comprised 67 subjects with morbid obesity scheduled for OAGB during the period from February 2015 to August 2018. Clinical, biological, and histologic data were evaluated pre and 15 months postoperatively. RESULTS: Fifteen months after surgery, a considerable reduction was noted in the grades of fat deposition, liver cell ballooning, and lobular inflammatory changes, in addition to the total NAS score. Fifteen months after surgery, nonalcoholic steatohepatitis (NASH) disappeared in 42% of the patients. A significant regression of fibrosis stage occurred after surgery in 79.1% of patients (p < 0.001). After surgery, patients had substantial reductions in aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, HbA1c, total cholesterol, and Low-density lipoprotein (p < 0.001, for all comparisons). Diabetes mellitus, hypertension, and dyslipidemia resolved in 54%, 59%, and 69% of the patients, respectively. CONCLUSION: OAGB resolved NASH from nearly 42% of patients and reduced the histological features of NAFLD 15 months after surgery. Bariatric procedures might be adopted as a therapeutic modality in severely obese cases with NAFLD after the failure of lifestyle modifications.