Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation? Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer. Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown. This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18-43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration. During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle. No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference -1.13, 95% CI -5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI -4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was -1.11 (95% CI -5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI -4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome. The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation. Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women's future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence. The study was supported by a grant (2011.WO23.C129) of 'Stichting Pink Ribbon', a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work. NTR4108. 6 August 2013. 30 January 2014.
Purpose: To compare pneumatic vitreolysis and pars plana vitrectomy in the management of focal symptomatic vitreomacular traction (VMT). Method : Patients aged 18 years or older, with idiopathic focal symptomatic VMT and best corrected visual acuity <20/40, without any other retinal pathology were randomized to undergo pneumatic vitreolysis (Group 1) or pars plana vitrectomy (Group 2). The primary outcome measure was resolution of traction confirmed with optical coherence tomography at 3 months. Secondary outcome measures were to compare changes in best corrected visual acuity, central foveal thickness, and complications if any. Result : A total of 30 eyes of 30 patients were included with 15 eyes in each group. Vitreomacular traction resolved successfully in 12 of 15 (80%) eyes in Group 1 and in all (100%) eyes in Group 2 (P = 0.224). The mean visual acuity improved from 0.80 ± 0.26 (20/126 Snellen"s equivalent) to 0.70 ± 0.46 logMAR (20/100 Snellen"s equivalent) in Group 1 (P = 0.71) and from 0.904 ± 0.44 (20/160 Snellen"s equivalent) to 0.47 ± 0.26 logMAR (20/59 Snellen"s equivalent) in Group 2 (P = 0.0016). Although 4 of 15 (26.66%) eyes in Group 1 had formation of full thickness macular hole and 7 eyes required resurgery (4 for full thickness macular hole and 3 for unresolved VMT), none in the pars plana vitrectomy group had any complications requiring resurgery (P = 0.0063). Two eyes in the pars plana vitrectomy group had intraoperative deroofing of the fovea leading to full thickness macular hole. Conclusion : Pars plana vitrectomy is better than pneumatic vitreolysis as a single intervention in the management of focal symptomatic VMT.
Purpose: To report updated clinical outcomes in subjects undergoing pars plana vitrectomy (PPV) using modern techniques and equipment for the treatment of proliferative diabetic retinopathy–related complications. Pooled analysis of five randomized clinical trials conducted at the same institution and included both study and control subjects from the trials. Method : There were 943 subjects who prospectively underwent small gauge PPV with antivascular endothelial growth factor pretreatment for proliferative diabetic retinopathy–related complications and completed 6 month follow up. Result : The visual acuity of the study population improved from median 2.00 (interquartile range 1.3, 2.3) at baseline to median 1.00 (interquartile range 0.5, 1.3) at 6 months. One hundred and eighty four patients (19.5%) achieved 20/50 or better acuity, and 652 patients (69.1%) achieved 20/200 or better acuity at 6 months. The vision improved or remained stable in 901 patients (95.5%), and 11 patients (1.2%) developed no light perception at 6 months. Intraoperative complications occurred in 343 cases (36.4%), and 199 cases (21.1%) experienced a postoperative complication. The most common postoperative complication was vitreous hemorrhage in 124 cases (62.3% of all complications). Unplanned secondary PPV was necessary in 86 cases (9.1%). Conclusion : This study reports updated clinical outcomes in patients undergoing PPV for proliferative diabetic retinopathy–related complications which compares favorably with the age before small gauge PPV and antivascular endothelial growth factor pretreatment.
Fernández Galván, LM, Casado, A, García Ramos, A, and Haff, GG. Effects of vest and sled resisted sprint training on sprint performance in young soccer players: A systematic review and meta analysis. J Strength Cond Res 36(7): 2023–2034, 2022—The aim of the meta analysis was to determine the effect of resisted sprint training (RST) on sprint performance in young (<20 years) soccer players and to analyze whether the training equipment (sled or vest) and magnitude of the resistive load (above or below 20% of body mass ) influences the long term adaptations in sprint performance. Resisted sprint training reduced the acceleration phase time , with greater reduction in sprint time occurring in response to applying resistance with a vest (SMD = −0.70) when compared with a sled (SMD = −0.27). Similar reductions were determined for resistive loads <20% (SMD = −0.55) and ≥20% of BM (SMD = −0.31). Full sprint time showed a small reduction after RST (SMD = −0.36), regardless of the training equipment (sled: SMD = −0.44; vest: SMD = −0.26) and resistive load (<20% of BM: SMD = −0.40 ≥ 20% of BM: SMD = −0.21). There was a small and nonsignificant reduction in the maximum velocity phase after RST (SMD = −0.25), which was comparable when the training was performed with vest (SMD = −0.34) or sled (SMD = −0.22). No significant differences in the changes of the acceleration phase time (SMD = 0.05) or full sprint time (SMD = 0.08) were observed between the experimental (sled or vest RST) and control groups (only soccer or unresisted sprint training). In conclusion, RST is effective to improve sprint performance in young soccer players, but the improvements are not superior to unresisted sprint training.
Handheld vital microscopy allows direct observation of red blood cells within the sublingual microcirculation. Automated analysis allows quantifying microcirculatory tissue perfusion variables - including tissue red blood cell perfusion (tRBCp), a functional variable integrating microcirculatory convection and diffusion capacities. We aimed to describe baseline microcirculatory tissue perfusion in patients presenting for elective noncardiac surgery and test that microcirculatory tissue perfusion is preserved during elective general anaesthesia for noncardiac surgery. Prospective observational study. University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 120 elective noncardiac surgery patients (major abdominal, orthopaedic or trauma and minor urologic surgery) and 40 young healthy volunteers. We measured sublingual microcirculation using incident dark field imaging with automated analysis at baseline before induction of general anaesthesia, under general anaesthesia before surgical incision and every 30 min during surgery. We used incident the dark field imaging technology with a validated automated analysis software. A total of 3687 microcirculation video sequences were analysed. Microcirculatory tissue perfusion variables varied substantially between individuals - but ranges were similar between patients and volunteers. Under general anaesthesia before surgical incision, there were no important changes in tRBCp, functional capillary density and capillary haematocrit compared with preinduction baseline. However, total vessel density was higher and red blood cell velocity and the proportion of perfused vessels were lower under general anaesthesia. There were no important changes in any microcirculatory tissue perfusion variables during surgery. In patients presenting for elective noncardiac surgery, baseline microcirculatory tissue perfusion variables vary substantially between individuals - but ranges are similar to those in young healthy volunteers. Microcirculatory tissue perfusion is preserved during general anaesthesia and noncardiac surgery - when macrocirculatory haemodynamics are maintained.
Up to 50% of patients presenting with stable, mainly exercise-induced, chest pain and 10-20% of those admitted to hospital with chest pain suggesting an acute coronary syndrome show normal or near-normal coronary arteries at angiography. Coronary microvascular dysfunction (CMD) is a major cause of symptoms in these patients. However, controversial data exist about their prognosis. In this article, we critically review characteristics and results of the main studies that assessed clinical outcome of patients with angina chest pain and nonobstructive coronary artery disease presenting with either a stable angina pattern or an acute coronary syndrome. Published data indicate that the patients included in most studies are heterogeneous and a major determinant of clinical outcome is the presence of atherosclerotic, albeit not obstructive, coronary artery disease. Long-term prognosis seems instead excellent in patients with totally normal coronary arteries and a syndrome of CMD-related stable angina (microvascular angina). On the other hand, the prognostic impact of CMD in patients presenting with an acute coronary syndrome needs to be better assessed in future studies.
Calprotectin is a protein molecule that is released from inflammatory cells. Measurement of calprotectin in various body fluids has recently gained significant importance for differentiating inflammatory and noninflammatory events. The subject has aroused interest in the field of nephrology and some renal pathologies in which urinary calprotectin levels have been studied. In this study, the measurement of urinary calprotectin level and its use for determining acute cisplatin nephrotoxicity in a group of patients with non-small cell lung cancer who received cisplatin-based oncological treatments have been investigated. The study included 41 patients who received cisplatin-based treatments for non-small cell lung cancer between January 2019 and January 2020. The patients were excluded from this study who were with estimated glomerular filtration rate (eGFR) 1.5 mg/dL, a history of urinary tract infection, and nephrotoxic drug use in the past month. Baseline and 48-hour sCr values and baseline, 6-hour, 12-hour, 24-hour, and 48-hour urinary calprotectin levels of all patients were measured. Four of the 41 patients who received cisplatin treatment were excluded because their 48-hour sCr values could not be accessed. The control group included 29 patients. While there was no difference between the cisplatin group and the control group in terms of baseline sCr and eGFR values, the cisplatin group had significantly higher urinary calprotectin values. Of the 37 patients treated with cisplatin, 7 (18.9%) developed cisplatin-induced nephrotoxicity. The comparison of groups with (group 1) and without cisplatin nephrotoxicity (group 2) showed comparable mean age and male sex ratio. Baseline sCr and eGFR values were similar in both groups. The cisplatin-induced nephrotoxicity group had significantly higher 48-hour sCr and significantly lower 48-hour eGFR values. Baseline, 12-hour, 24-hour, and 48-hour urinary calprotectin levels were similar in groups with and without cisplatin nephrotoxicity. Recent studies have demonstrated that urinary calprotectin level measurement can be used to distinguish intrinsic acute kidney disease from prerenal kidney disease. However, the comparison of groups with and without cisplatin nephrotoxicity in our study showed no difference in urinary calprotectin levels. However, there is a need for large-scale studies using combined urinary biomarkers.
Interleukin 7 (IL-7) has been demonstrated regulating lymphangiogenesis, apoptosis, and proliferation. Whether IL-7 induce or inhibit autophagy in non-small cell lung cancer (NSCLC) are unknown. In this study, Western blot was used to detect cytoplasmic and nuclear protein of p53, total protein of AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and Light chain 3 (LC3). Quantitative Real-Time PCR (qRT-PCR) was used to detect p53 mRNA level after treated with IL-7. Then using transmission electron microscopy to observe the morphological change of autophagosome. 123 cases of NSCLC were collected for survival analysis, immunohistochemistry staining and cox regression multivariate analysis. We find that IL-7 induce the p53 translocation from nucleus to cytoplasm, then IL-7 down-regulate phosphorylation of AMPK and up-regulate phosphorylation of mTOR. The expression of AMPK and p53 were associated with IL-7/IL-7R and mTOR expression. Clinically, AMPK and p53 were well correlated with stage and survival of lung cancer patients. IL-7R, mTOR and tumor stage were the strongest predictors of survival. In conclusion, IL-7 inhibit autophagy in NSCLC via P53 regulated AMPK/mTOR signaling pathway. AMPK and p53 are correlated with patients' survival. IL-7R, mTOR and tumor stage are the strongest predictor of survival.
The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA NEAT1 as a molecular trigger for ALYREF effects in breast cancer. Mechanistically, we found that ALYREF binds to the NEAT1 promoter region to enhance the global NEAT1 transcriptional activity. Importantly, by stabilizing CPSF6, a protein that selectively activates the post-transcriptional generation of the short isoform of NEAT1, as well as by direct binding and stabilization of the short isoform of NEAT1, ALYREF selectively fine-tunes the expression of the short NEAT1 isoform. Overall, our study describes ALYREF as a novel factor contributing to breast carcinogenesis and identifies novel molecular mechanisms of regulation the two isoforms of NEAT1.
Maladaptive changes of nerve injury-associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury-specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury-induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury-induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.
The last known red wolves were captured in southwestern Louisiana and eastern Texas in 1980 to establish a captive breeding population. Before their extirpation, gene flow with coyotes resulted in the persistence of endangered red wolf genetic variation in local coyote populations. We assessed genomic ancestry and morphology of coyotes in southwestern Louisiana. We detected that 38 to 62% of the coyote genomes contained red wolf ancestry acquired in the past 30 years and have an admixture profile similar to that of the canids captured before the extirpation of red wolves. We further documented a positive correlation between ancestry and weight. Our findings highlight the importance of hybrids and admixed genomes as a reservoir of endangered species ancestry for innovative conservation efforts. Together, this work presents an unprecedented system that conservation can leverage to enrich the recovery program of an endangered species.
Background Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of pancreatic malignancies. Surgical resection is the only curative treatment option for patients with localized PanNETs, yet the role of cancer directed surgery (CDS) in the setting of oligometastatic liver metastasis remains a controversy. Method All patients diagnosed with PanNETs and liver only metastasis from 2010 to 2018 were identified from the SEER database. The biases of baseline characteristics between CDS and no CDS cohorts were reduced by the propensity score matching (PSM) method, and the prognostic role of CDS was estimated using the Kaplan–Meier method and Cox regression models. Logistic regression analysis was utilized to identify factors associated with patients who underwent CDS. Result A total of 1,270 PanNET patients with oligometastatic liver metastasis were included and analyzed. Of these patients, 283 (22.3%) patients underwent CDS of the primary tumor, while the remaining 987 (77.7%) did not. The OS and CSS were significantly better in the CDS cohort regardless of the propensity score analysis. Multivariate analysis revealed that age, tumor differentiation, tumor location, and lymph node status were significantly associated with patients who were more likely to receive CDS. Conclusion Our study demonstrated that CDS was associated with survival benefits in selected patients with PanNETs and liver only metastasis based on a large population database.
(This summary has been generated by AI. Generate your own summaries: https://www.welcome.alviss.ai/alboard/#/editorial) Background : the human exposure to toxic chemicals and heavy metals is one of the main predisposing factors contributing to male infertility. The purpose of the present study was to investigate and compare the curative effect of coenzyme q10, lycopene, l carnitine, and zinc sulfate against the cadmium induced infertility in male wistar rats. Method : cadmium chloride was orally administered to rats for three consecutive days. Then, oral administration of different treatments was carried out for 30 days. Result : treatment with LC, LC and LC coq10 improved progressive sperm motility and other parameters and increased SOD, GSH, and cat in the rat testes. Conclusion : the administration of lycopenes and a high dose combination of LC-10 were more efficacious in treating cadmulation induced infertility than other treatments.
This study was to investigate the role of microRNA-29a-3p (miR-29a-3p) in human bone marrow mesenchymal stem cells (hBMSCs), and its relationship with steroid-associated osteonecrosis. The online tool GEO2R was used to screen out the differentially expressed genes (DEGs) in GSE123568 dataset. Quantitative real time-polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-29a-3p, forkhead box O3 (FOXO3), alkaline phosphatase (ALP), bone gamma-carboxyglutamate protein (OCN) and RUNX family transcription factor 2 (Runx2) in the hBMSCs isolated from the patients with steroid- associated osteonecrosis. CCK-8 assay was executed to measure cell viability; western blot assay was utilized to detect FOXO3, ALP, Runx2, OCN and β-catenin expression. Cell apoptosis and cell cycle were detected by flow cytometry. Immunofluorescence assay was used to detect the sub-cellular localization of β-catenin. Bioinformatics analysis and luciferase reporter gene assay were performed to confirm whether miR-29a-3p can combine with FOXO3 3'UTR. MiR-29a-3p was markedly up-regulated in the hBMSCs of patients with steroid-associated osteonecrosis, while FOXO3 mRNA was significantly down-regulated. Transfection of miR-29a-3p mimics significantly inhibited the hBMSCs' proliferation, osteogenic differentiation markers' expressions, including ALP, Runx2, OCN, and repressed the ALP activity, as well as promoted cell apoptosis and cell-cycle arrest. FOXO3 was identified as a target gene of miR-29a-3p, and miR-29a-3p can inhibit the expression of FOXO3 and β-catenin, and inhibition of miR-29a-3p promoted translocation of β-catenin to the nucleus. MiR-29a-3p can modulate FOXO3 expression and Wnt/β-catenin signaling to inhibit viability and osteogenic differentiation of hBMSCs, thereby promoting the development of steroid-associated osteonecrosis.
This updated systematic review and meta-analysis investigates the putative role of the appendix in ulcerative colitis as a therapeutic target. Ovid Medline, Embase, PubMed and CENTRAL were searched with MeSH terms ("appendectomy" OR "appendicitis" OR "appendix") AND ("colitis, ulcerative") through October 2020, producing 1469 references. Thirty studies, including 118 733 patients, were included for qualitative synthesis and 11 for quantitative synthesis. Subgroup analysis was performed on timing of appendicectomy. Result are expressed as odds ratio (OR) with 95% confidence intervals (CIs). Appendicectomy before UC diagnosis reduces the risk of future colectomy (OR, 0.76; 95% CI, 0.65-0.89; I2 = 5%; P = .0009). Corresponding increased risk of colorectal cancer and high-grade dysplasia are identified (OR, 2.27; 95% CI, 1.11-4.66; P = .02). Significance is lost when appendicectomy is performed after disease onset. Appendicectomy does not affect hospital admission rates (OR, 0.87; 95% CI, 0.68-1.12; I2 = 93%; P = .27), steroid use (OR, 1.08; 95% CI, 0.78-1.49; I2 = 36%; P = .64), immunomodulator use (OR, 1.04; 95% CI, 0.76-1.42; I2 = 19%; P = .79), or biological therapy use (OR, 0.76; 95% CI, 0.44-1.30; I2 = 0%; P = .32). Disease extent and risk of proximal progression are unaffected by appendicectomy. The majority (71% to 100%) of patients with refractory UC avoid colectomy following therapeutic appendicectomy at 3-year follow-up. Prior appendicectomy reduces risk of future colectomy. A reciprocal increased risk of CRC/HGD may be due to prolonged exposure to subclinical colonic inflammation. The results warrant further research, as consideration may be put toward incorporating a history of appendicectomy into IBD surveillance guidelines. A potential role for therapeutic appendicectomy in refractory left-sided UC is also identified. This article was written as part of a higher degree with the University of Edinburgh. The first author received the Association of Surgeons in Training (ASiT) Edinburgh Surgery Online Bursary during the completion of the degree and this journal article. This updated systematic review finds appendicectomy before ulcerative colitis (UC) diagnosis reduces risk of future colectomy but increases the risk of colorectal malignancy. Incorporating a history of appendicectomy into IBD surveillance guidelines could be considered. A potential role for therapeutic appendicectomy in left-sided treatment refractory UC is also identified.
CD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine and costimulatory receptors. Nutrient availability also impacts T cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types.
Molecular Pain, Volume 18, Issue , April 2022. Cyclin dependent kinase 5 (Cdk5) is a key neuronal kinase whose activity can modulate thermo , mechano , and chemo nociception. Cdk5 can modulate nociceptor firing by phosphorylating pain transducing ion channels like the transient receptor potential vanilloid 1 (TRPV1), a thermoreceptor that is activated by noxious heat, acidity, and capsaicin. TRPV1 is phosphorylated by Cdk5 at threonine 407 (T407), which then inhibits Ca2+ dependent desensitization. To explore the in vivo implications of Cdk5 mediated TRPV1 phosphorylation on pain perception, we engineered a phospho null mouse where we replaced T407 with alanine (T407A). The T407A point mutation did not affect the expression of TRPV1 in nociceptors of the dorsal root ganglia and trigeminal ganglia (TG). However, behavioral tests showed that the TRPV1T407A knock in mice have reduced aversion to oral capsaicin along with a trend towards decreased facial displays of pain after a subcutaneous injection of capsaicin into the vibrissal pad. In addition, the TRPV1T407A mice display basal thermal hypoalgesia with increased paw withdrawal latency while tested on a hot plate. These results indicate that phosphorylation of TRPV1 by Cdk5 can have important consequences on pain perception, as loss of the Cdk5 phosphorylation site reduced capsaicin and heat evoked pain behaviors in mice.
Algorithms, Vol. 15, Pages 229: Privacy Preserving Feature Selection with Fully Homomorphic Encryption Algorithms doi: 10.3390/a15070229 Authors: Shinji Ono Jun Takata Masaharu Kataoka Tomohiro I Kilho Shin Hiroshi Sakamoto For the feature selection problem, we propose an efficient privacy preserving algorithm. Let D, F, and C be data, feature, and class sets, respectively, where the feature value x(Fi) and the class label x(C) are given for each x∈D and Fi∈F. For a triple (D,F,C), the feature selection problem is to find a consistent and minimal subset F′⊆F, where consistent means that, for any x,y∈D, x(C)=y(C) if x(Fi)=y(Fi) for Fi∈F′, and minimal means that any proper subset of F′ is no longer consistent. On distributed datasets, we consider feature selection as a privacy preserving problem: assume that semi honest parties A and B have their own personal DA and DB. The goal is to solve the feature selection problem for DA∪DB without sacrificing their privacy. In this paper, we propose a secure and efficient algorithm based on fully homomorphic encryption, and we implement our algorithm to show its effectiveness for various practical data. The proposed algorithm is the first one that can directly simulate the CWC (Combination of Weakest Components) algorithm on ciphertext, which is one of the best performers for the feature selection problem on the plaintext.