Class IA Research Articles

Patient characteristics and periprocedural outcomes of percutaneous coronary intervention of the left main coronary artery

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Left main (LM) disease is found in 5 to 6% of all coronary angiograms. Revascularization has a class IA recommendation, but the choice of the revascularization method whether by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) is currently under debate. The selection depends on patient’s characteristics (age, sex, comorbidities, frailty), as well as anatomical considerations. We aim to describe the patients with LM disease that were treated with PCI and report their short-term outcomes in a tertiary center. Methods Single-center retrospective study including all patients who underwent LM PCI from 2013 to 2019. The basal characteristics were retrieved from the electronic medical records. Acute kidney injury was defined as an absolute increase in serum creatinine of ≥ 0.3 mg/dL or ≥ 1.5-fold from baseline. Type IVa myocardial infarction was assessed by the Third Universal Definition. Results A total of 110 procedures were performed during the study period (table 1). Most of the patients were male, with a median age of 61 years. A considerable number of patients showed a reduced ejection fraction (41.2%). The left main lesions were most frequently distal and associated with left anterior descending artery disease. Radial access was used in a minority of cases (33.6%), although most were IVUS-guided (93.6%). Complete revascularization was achieved in 55.5%. The number of procedures over time is depicted in figure 1. There was only 1 death (0.9%) during index hospitalization. There was a high incidence of type IVa myocardial infarction (19.1%) and acute kidney injury (10%), and a low incidence of TIMI major bleeding (1.8%). Conclusion Current practice shows an increase of left main PCI over time, particularly from 2016, after the EXCEL trial results were published. This can be due to improved technical aspects such as IVUS guidance, which was used in most patients. Noticeable, almost half of the patients had a reduced ejection fraction. Although there was a very low short-term mortality associated with the procedure (1%), as well as a low bleeding risk (4.8%), there was a high incidence of type IVa myocardial infarction (20.2%). Only 55.5% archived a complete revascularization. Despite promising immediate results in clinical practice, long term follow up will be essential to determine the future role of left main PCI.

Structural Investigation of Allosteric Regulation in Class III Ribonucleotide Reductases

Ribonucleotide reductases (RNRs) are essential enzymes that use radical‐based chemistry to catalyze the reduction of ribonucleotides to deoxyribonucleotides. Each RNR class uses a different cofactor to generate a catalytically‐essential thiyl radical species in the enzyme active site. Anaerobic (class III) RNRs employ an oxygen‐sensitive glycyl radical cofactor installed within the glycyl radical domain (GRD) that is adjacent to the active site, whereas aerobic (class Ia) RNRs employ long‐range radical transfer between the catalytic subunit and a di‐iron/tyrosyl radical cofactor housed in the b2 subunit. To maintain intracellular nucleotide pool balance, RNRs are allosterically regulated. For the prototypical class Ia RNRs from Escherichia coli, this allosteric activity regulation involves dATP binding to the N‐terminus of the catalytic subunit in a region known as the ‘cone domain’, resulting in an association between the cone domain and the b2 subunit that prevents radical transfer between subunits. Despite not requiring a b2 subunit, some class III RNRs (e.g. Streptococcus thermophilus)have a cone domain and are allosterically inhibited by dATP. In this study, we investigate allosteric activity regulation for such a class III RNR, the class III RNR from Streptococcus thermophilus(StNrdD). We use a newly developed LC‐MS/MS based activity assay to show that dATP downregulates StNrdD activity and ATP upregulates activity as is true for class Ia RNRs. Using crystallography, we obtain structural data showing that ATP and dATP both bind to the cone domain, and that both the cone domain and GRD are flexible. In particular, in one monomer of StNrdD dimer, the cone domain contacts the GRD, and both domains are ordered, and in the other monomer, the cone domain is positioned away from the GRD and the GRD is disordered. These observations led us to hypothesize that the cone domains of class III RNRs, like those of class Ia RNR, regulate activity through promotion or inhibition of the radical transfer step, but instead of controlling the position of b2, the position of the GRD is allosterically regulated. In this presentation, we show the data described above and show recent cryogenic electron microscopy of ATP‐bound and dATP‐bound states of StNrdD, which reveals differential positioning of the cone domains in the presence of these allosteric effectors. We also present our current thinking about the mechanism of allosteric regulation of activity in a class III RNR.

Biochemical Characterization of a Human Ribonucleotide Reductase (HsRNR) Variant Lacking Activity Regulation

Ribonucleotide reductase (RNR) is responsible for the synthesis of deoxyribonucleotides used in DNA synthesis and repair. Class Ia RNRs are composed of two dimeric subunits: a catalytic subunit (α2) which contains the active site and two allosteric regulation sites, and radical generating (β2) subunit housing the diferric‐tyrosyl radical cofactor. The two subunits form an α2β2 heterotetrametric complex that allows the radical to travel from β to α subunit for catalysis. RNR activity is regulated by the binding of ATP/dATP to an N‐terminal cone domain. Human RNRs (HsRNRs) are class Ia enzymes that form a homohexameric α6in the presence of either dATP or ATP. Although, both α6 assemblies are morphologically identical, only the α6‐ATP can be disturbed by the addition of β to form the α2β2 complex necessary for catalysis. Recent studies have shown that α subunits contact each other via their cone domains in the α6 rings, but it is unknown if the cone domains contact β2 in the α2β2 active complex. Here, we aim to probe the role of the cone domains in catalysis through biochemical and biophysical studies of an α subunit variant lacking the cone domain. We used site‐directed mutagenesis to delete residues 2‐92 of α, and expressed and purified the variant a protein. The variant protein was used for HPLC‐MS based activity assays of HsRNR. Preliminary results show the cone domain is important for catalysis. Understanding more about RNR’s structure and activity regulation can facilitate development of new cancer therapies.

Abstract 178: Improving Cardiac Rehab Attendance By Providing Transportation Services And Removing Cost

For more than a decade, Cardiac Rehabilitation (CR) has been a Class IA indication for cardiovascular patient populations. While the benefits of CR are well published, enrollment and attendance barriers persist. The overall objective of the PACE Project is to increase enrollment and completion of a CR program in an urban academic health center. It addresses two known barriers to patient CR participation: transportation and affordability. Our hypothesis is that Phase II CR enrollment and attendance can be increased by providing free transportation and removing patient out-of-pocket expenses. The study recruitment period was October 2019 to March 2021, with a pause in services and recruitment during the initial COVID-19 pandemic lockdown. Patient were offer PACE participation during their hospitalization. Once consents were obtained, the standard processes to schedule and enroll in Phase II cardiac rehab and exercise prescription were adhered. Patients were responsible for calling and scheduling transportation services for their CR sessions. Upon completion of the study, 73% (41/56) patients attended at least one Phase II session, with an average of 15 session per attendee. This compared to previously published national participation of 8.2% or 32.6%, of at least one session, depending upon in-patient CR referral. The study had a Phase II graduation rate of 32% (13/41). Transportation was utilized in 10.7% (6/56) of participants, with billed mileage ranging from 1-5 miles. Those utilizing transportation services were all female, with 83% (5/6) being women of color. Out-of-pocket co-payments were observed for 41.4% (17/41) of attendees. For those with co-payments, an average of $40, with a range $2-$60, per session was observed. CR is a proven guideline directed intervention to reduce secondary cardiac events. Our study suggest the removal of frequently cited barriers to participation, cost and transportation, is associated with improved CR participation.

The characterization of MCMV specific Qa-1-restricted CD8+ T cells

Abstract While MHC class Ia-restricted classical CD8+ T cells have been widely shown to participate in the immune response to viral infection, little is known about the MHC class Ib-restricted non-classical CD8+ T cell response. Our laboratory recently demonstrated that during murine cytomegalovirus (MCMV), a well-established model system for human CMV, adoptively transferred non-classical CD8+ T cells are sufficient to protect KbDb RAG1−/− mice from lethality. We sought to further characterize this protective population, which is largely Qa-1-restricted. Using KbDb−/− and KbDb−/−. SJL mice, we are able to track the same original population of T cells through iterative adoptive transfers in multiple hosts. Following MCMV infection of new hosts, these T cells continue to play an active role in viral protection and exhibit both effector and memory phenotypes. Strikingly, following multiple challenges, an enriched clonal CD8+ T cell response is observed. While certain strains of human CMV encode a mimic of the canonical peptide binding partner for Qa-1, MCMV does not have a similar mechanism. Rather, our data show that these T cells are stimulated by an MCMV-derived antigen that is recognized by CD8+ T cells with limited αβ TCR diversity. The population we describe may act as a compensatory immune mechanism when MHC class Ia is targeted by CMV immunoevasins. Taken together, these data demonstrate that an MCMV-derived peptide is presented by Qa-1, necessary for an MCMV-specific activation of non-classical CD8+ T cells, and may be of importance for viral protection when classical CD8+ T cell immunity is compromised. This work is supported by NIH Research Grants AI046709 and AI12221, and was supported by a T32 Training Grant in Molecular and Cell Biology and Biochemistry in years 2019-2020. Shanelle Reilly is also supported by research supplement R01 3AI046709-18S1 to promote diversity.

A suicide diiron oxygenase in p‐aminobenzoate biosynthesis in Chlamydia trachomatis

Folate is an essential one‐carbon carrier cofactor required for essential biological reactions such as amino acid and DNA biosynthesis. Folates are comprised of three chemical moieties: a pteridine ring, p‐aminobenzoate (pABA), and glutamate residues. Chlamydia trachomatis has been shown to synthesize folate de novo; however, it is missing several genes involved in the canonical folate biosynthesis pathway. Previous work has demonstrated that a single gene, ct610, functionally replaces the enzymes responsible for pABA production in the canonical biosynthesis pathway. However, CT610 does not use chorismate as the precursor to pABA as is used in the canonical pathway. Further experiments showed that isotopically labeled tyrosine was incorporated into the pABA molecule when synthesized by CT610 in vivo. However, in vitro experiments demonstrated that CT610 produces pABA in the presence of oxygen and a reducing agent without any added substrates, including tyrosine. This led to the hypothesis that CT610 is a self‐sacrificing “suicide” enzyme that donates an active site tyrosine residue in synthesizing pABA. CT610 has low sequence similarity to non‐heme diiron monooxygenases such as methane monooxygenase and class Ia ribonucleotide reductase, and the previously solved crystal structure of CT610 revealed a diiron active site. Here we describe our recent progress towards understanding this unique suicide mechanism for pABA biosynthesis. To determine the tyrosine residue sacrificed in the reaction, we generated five active site tyrosine to phenylalanine mutants and found that two of the variants completely abolished pABA production, suggesting that one of these residues is the precursor to pABA. Further, a conserved lysine residue is also essential for the reaction and may be a sacrificial amino group donor. We have confirmed the oxygenase activity of wild‐type CT610, which requires only a reducing agent and is not stimulated by the presence of tyrosine or other possible substrates. Further, we developed an Fe(II) reconstitution procedure, where the reconstituted enzyme exhibits a drastic increase in oxygenase activity. However, surprisingly, the reconstituted enzyme does not exhibit increased pABA synthase activity, although EDTA treatment of the as‐purified enzyme almost completely inhibits pABA production. This suggests that a metal other than iron is required for the reaction and thus current work is focused on testing other potential metal cofactors that may play a role in the novel suicide reaction.

The importance of cardiorehabilitation in the era of modern treatment of cardio-vascular diseases

Cardiac rehabilitation (CR) has a class IA indication in international and national guidelines as an intervention with proven efficacy for decreasing cardiovascular and all-cause mortality in various categories of cardiological patients. However, CR is one of the least used current technologies for the treatment of patients with cardiovascular diseases worldwide. This article presents the state of the CR problem during the epoch of high-tech treatments of cardiovascular diseases; the prevalence of using CR in various countries; traditional and new methodological approaches, including telemedicine; and clinical and prognostic effects of CR in various categories of patients with cardiovascular diseases.

Analysis of Teacher's Efforts in Improving Students' Calistung (Read-Write-Arithmetic) Skills During the Transition Period/Analisis Upaya Guru Dalam Meningkatkan Keterampilan Calistung (Baca-Tulis-Aritmatika) Siswa Selama Masa Transisi

Teachers must provide stimulus to students to be able to achieve optimal learning outcomes. One of them is a stimulus in learning Calistung (reading, writing, and arithmetic) because this Calistung is a milestone for lifelong learning. During the pandemic, learning is carried out online and face-to-face, which is limited because it must be following strict health protocols. Therefore, this study aims to analyze the efforts made by teachers in improving the calistung skills of class IA students at MIN 2 Banjarmasin. The results obtained in this study are the teacher's efforts in improving students' Calistung skills, the teacher plans to learn well through making lesson plans; using learning models, strategies, and methods that enable students to actively participate in learning; holding games that support Calistung learning; provide motivation to increase students' enthusiasm for learning, and provide additional study hours for students who need more guidance in Calistung.

Computational study reveals substituted benzimidazole derivatives' binding selectivity to PI3Kδ and PI3Kγ.

Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors.

ANALISIS YURIDIS PENGARUH USIA TERHADAP TINGGINYA TINGKAT PERCERAIAN DI KOTA BATAM (STUDI PENELITIAN DI PENGADILAN AGAMA KELAS IA BATAM)

This journal is entitled Juridical Analysis of the Effect of Age on the High Level of Divorce in Batam City (Research Study at the Religious Court Class Ia Batam) on Jalan RE. Martadinata Number 5, Sekupang, Batam City, Riau Islands 29425, with the construction problems: What are the legal arrangements regarding filing for divorce at the Batam Class IA Religious Court?; and what are the factors behind the high divorce rate in Batam and what are the solutions to reduce the high divorce rate? The qualification/type of writing for this journal uses a normative legal writing type, which is supported by sociological/empirical legal research. To analyze some of the problems in this journal, a big theory (The Pure Theory of Law) is used. Legal positivism (positive law school) which sees the need to clearly separate law and morals (between applicable law and the law that should be), and theory (Law is Command of a Lawgiver) John Austin, namely the law is considered as a logical system, fixed and closed (closed logical system), the law is strictly separated from justice and is not based on good and bad values. Legal arrangements regarding filing for divorce in the Religious Courts refer to Law Number 1 of 1974 concerning Marriage, Government Regulation of the Republic of Indonesia Number 9 of 1975 concerning the Implementation of Law Number of 1974 concerning Marriage, Law Number 32 of 1954 concerning Enforcement of Laws - Law of the Republic of Indonesia dated November 21, 1946 Number 22 of 1946 concerning Registration of Marriage, Divorce, Reconciliation in All Regions Outside Java and Madura, Instruction of the President of the Republic of Indonesia Number 1 of 1991 concerning the Dissemination of Compilation of Islamic Law, Law of the Republic of Indonesia Number 3 of 2006 concerning Amendments to Law Number 7 of 1989 concerning Religious Courts.Keywords: Marriage, Divorce, Age Effect.

MiR-92a/KLF4/p110\u03b4 regulates titanium particles-induced macrophages inflammation and osteolysis

As total joint replacement is widely applied for severe arthropathy, peri-prosthetic aseptic loosening as one of the main causes of implant failure has drawn wide attention. Wear particles such as titanium particles (TiPs) derived from prosthesis can initiate macrophages inflammation and sequentially activate osteoclasts, which results in bone resorption and osteolysis for long-term. Therefore, inhibiting wear particles induced macrophages inflammation is considered as a promising therapy for AL. In this research, we found that the inhibition of p110δ, a member of class IA PI3Ks family, could significantly dampen the TiPs-induced secretion of TNFα and IL-6. By the transfection of siRNA targeting p110δ, we confirmed that p110δ was responsible for TNFα and IL-6 trafficking out of Golgi complex without affecting their expression in TiPs-treated macrophages. As the upstream transcription-repressor of p110δ, Krüppel-like factor 4 (KLF4), targeted by miR-92a, could also attenuate TiPs-induced inflammation by mediating NF-κB pathway and M1/M2 polarization. To further ascertain the roles of KLF4/p110δ, TiPs-induced mice cranial osteolysis model was established and vivo experiments validated that KLF4-knockdown could exacerbate TiPs-induced osteolysis, which was strikingly ameliorated by knockdown of p110δ. In summary, our study suggests the key role of miR-92a/KLF4/p110δ signal in TiPs-induced macrophages inflammation and osteolysis.

Benefits and Risks of Epilepsy Surgery in Patients With Focal Cortical Dysplasia Type 2 in the Central Region.

Focal cortical dysplasia type 2 (FCD2) in the central region can cause drug-resistant epilepsy for which surgery remains challenging because of subsequent functional deficits. Advances in imaging and surgical techniques have progressively improved outcome. We aimed to assess the benefits on epilepsy and the functional risks after FCD2 resections in these highly eloquent areas. We retrospectively studied all consecutive patients with histologically confirmed FCD2 located in the central region operated on between 2000 and 2019 at a single center. We analyzed electroclinical and imaging features (including fMRI), seizure outcome, and early and late postoperative neurologic status correlating to anatomo-functional areas (primary motor cortex [PMC], paracentral lobule [PCL], supplementary motor area [SMA], precentral gyrus [PrCG], postcentral gyrus [PoCG], central operculum [COp]). Sixty patients (35 female, age 7-65 years) were included in the study. Epilepsy was characterized by early onset, high seizure frequency with clusters (30-90/d), drop attacks, and status epilepticus. Ictal semiology included sensory-motor auras, motor and postural manifestations, and postictal motor deficits. EEG and stereo-EEG patterns were like those typically recorded in FCD2. MRI was positive in 63% and 18F-fluorodeoxyglucose-PET was positive in 86% of the patients. fMRI demonstrated activations close to the FCD2 (59%) or minor reorganization (41%) but none within the lesion. Seizure-free outcome (2- to 20-year follow-up) was obtained in 53 patients (88%), including 37 achieving Engel class IA (62%), correlating with complete FCD2 removal. Early transitory postoperative deficits occurred in 52 patients (87%), which were severe in 19, mostly after PMC, PCL, and SMA resections, while PrCG, PoCG, and COp resections were associated with minor/moderate deficits. Total recovery was observed in 21 of 52 patients (40%), while a permanent deficit (>2 years) persisted in 31 (minor 19, moderate 9, major 3). The best outcome (seizure freedom without deficit [48%] or with minor deficit (28%]) was significantly more frequent in children (p = 0.025). Antiseizure medications were discontinued in 28 patients (47%). Quality of life correlated with seizure-free outcome and absence of postoperative deficit; 43 patients (72%) reported a schooling or socio-professional improvement. Excellent seizure outcome and low rates of major permanent disability can be achieved after central FCD2 resections despite functional risks. Due to its retrospective nature, this study provides Class IV evidence that good seizure outcomes with minor additional deficits can be achieved after epilepsy surgery in the central region.

A Leucyl-tRNA Synthetase Urzyme: Authenticity of tRNA Synthetase Catalytic Activities and Promiscuous Phosphorylation of Leucyl-5'AMP.

Aminoacyl-tRNA synthetase (aaRS)/tRNA cognate pairs translate the genetic code by synthesizing specific aminoacyl-tRNAs that are assembled on messenger RNA by the ribosome. Deconstruction of the two distinct aaRS superfamilies (Classes) has provided conceptual and experimental models for their early evolution. Urzymes, containing ~120–130 amino acids excerpted from regions where genetic coding sequence complementarities have been identified, are key experimental models motivated by the proposal of a single bidirectional ancestral gene. Previous reports that Class I and Class II urzymes accelerate both amino acid activation and tRNA aminoacylation have not been extended to other synthetases. We describe a third urzyme (LeuAC) prepared from the Class IA Pyrococcus horikoshii leucyl-tRNA synthetase. We adduce multiple lines of evidence for the authenticity of its catalysis of both canonical reactions, amino acid activation and tRNALeu aminoacylation. Mutation of the three active-site lysine residues to alanine causes significant, but modest reduction in both amino acid activation and aminoacylation. LeuAC also catalyzes production of ADP, a non-canonical enzymatic function that has been overlooked since it first was described for several full-length aaRS in the 1970s. Structural data suggest that the LeuAC active site accommodates two ATP conformations that are prominent in water but rarely seen bound to proteins, accounting for successive, in situ phosphorylation of the bound leucyl-5′AMP phosphate, accounting for ADP production. This unusual ATP consumption regenerates the transition state for amino acid activation and suggests, in turn, that in the absence of the editing and anticodon-binding domains, LeuAC releases leu-5′AMP unusually slowly, relative to the two phosphorylation reactions.

Effectiveness of Sela's Decision in Article 96 Law Number 2 of 2004 on the Resolution of Industrial Relations Disputes

Disputes in the industrial sector have led to problems in settlement by judges and legal imbalances in law enforcers and society. The objective of this research was to discuss the effectiveness of the implementation of interlocutory decisions in the Gresik Class IA Industrial Relations Court, where there has been a mismatch between the substance, namely the law regarding interlocutory decisions, and the legal structure, namely law enforcers who in this case are judges. This was juridical-empirical research that used a case research approach and descriptive analysis was used. The results demonstrated that the ineffectiveness of the interlocutory decision in Article 96 of the PPHI Law at PHI Gresik was due, first, to the inconsistency of the legal sources used during the payment process of wages between the Constitutional Court and SEMA. Second, the judges felt fear and doubt in fulfilling the justice of the parties when passing the interlocutory decision and fulfilling the workers’ lawsuit; however, in the final decision, the employer ultimately won. Third, there was no explanation for the evidentiary requirements for the delivery of the interlocutory decision in the PPHI Law, which was different from the decision in the District Court on Civil Law. The problems with interlocutory decisions will lead to imperfect application of the law, in terms of the substance of the law, the practice of the law enforcers, and the culture of society.
 Keywords: effectiveness, interlocutory verdict, industrial relations disputes

Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity

The non-classical class Ib molecule human leukocyte antigen E (HLA-E) has limited polymorphism and can bind HLA class Ia leader peptides (VL9). HLA-E-VL9 complexes interact with the natural killer (NK) cell receptors NKG2A-C/CD94 and regulate NK cell-mediated cytotoxicity. Here we report the isolation of 3H4, a murine HLA-E-VL9-specific IgM antibody that enhances killing of HLA-E-VL9-expressing cells by an NKG2A+ NK cell line. Structural analysis reveal that 3H4 acts by preventing CD94/NKG2A docking on HLA-E-VL9. Upon in vitro maturation, an affinity-optimized IgG form of 3H4 showes enhanced NK killing of HLA-E-VL9-expressing cells. HLA-E-VL9-specific IgM antibodies similar in function to 3H4 are also isolated from naïve B cells of cytomegalovirus (CMV)-negative, healthy humans. Thus, HLA-E-VL9-targeting mouse and human antibodies isolated from the naïve B cell antibody pool have the capacity to enhance NK cell cytotoxicity.

PREDICTION ANALYSIS OF DIVORCE RATE USING THE DECISION SUPPORT SYSTEM METHOD

The existence of divorce actually results in the separation of husband and wife bonds. This study aims to examine and examine the influence of divorce factors in the city of Padang. In this problem, the author predicts the divorce rate that will occur in the city of Padang in 2021 by reviewing divorce data in 2020. The method used in this study is normative juridical research by conducting observations, field notes, and interviews with related parties at the research location. . The results of this study will provide benefits for the Padang Class IA Religious Court to make a breakthrough that is able to reduce the divorce rate. The analysis in this problem also uses two methods of decision support systems, namely Single Moving Average (SMA) and Analytical Hierarchy Process (AHP). Based on manual calculations, the researcher can conclude that continuous disputes in the household can trigger divorce. Therefore, the Padang Class IA Religious Court can make a breakthrough in the form of education about the impact of divorce and education in solving a problem. The application of the Single Moving Average method can predict accurately for January 2021 as many as 96 cases for 5 period predictions with a MAPE of 11%. In the calculation of the Analytical Hierarchy Process method, the final calculation is 0.32 which shows that continuous disputes can lead to divorce.

Minor oral surgery on impacted lower third molar done by IIUM Undergraduates: a retrospective study

Minor oral surgery (MOS) is one of the important requirements for dental undergraduates to perform in Kulliyyah of Dentistry, IIUM. However, no assessment has been done on the suitability of the cases received by the students. Thus, this study was aimed to describe type of cases and level of difficulty in relation to undergraduate year of study. This study consisted of 97 subjects who had undergone MOS by IIUM undergraduate from September 2014 to October 2015. Data was collected from patient’s documentation and orthopantomogram. Pederson index and relationship to inferior dental nerve were used to determine the difficulty index level. Statistical analysis was done using Chi-square test with statistical significance set at p? 0.05. The mean age of the patients was 24 years old, with male to female ratio 1:1.9. 52.6% of the cases were indicated for surgery due to recurrent pericoronitis. The types of cases mostly received by undergraduates were Class IA (30.9%) and Class IIA (48.5%) with mesioangular impaction (39.2%). Year 4 students received more difficult cases compared to Year 5 (p = 0.504) with less complications postoperatively. Dental undergraduates received simple to moderate cases for MOS, and no significant association was found between year of undergraduate study and difficulty level of the cases.

HLA Class Ib-receptor interactions during embryo implantation and early pregnancy.

Although the immune system intuitively must have an important role in embryo implantation and in the achievement of a pregnancy, the molecular details have for long been controversial. The role of the human leukocyte antigen (HLA) system has been debated. The unique HLA expression profile of the HLA Class Ia molecule HLA-C and the HLA Class Ib molecules HLA-E, HLA-F and HLA-G at the feto-maternal interface is now recognized. However, HLA Class Ib molecules may also have a role in embryo implantation and pregnancy success. The aim of this review was to evaluate the literature and recent discoveries on the role of the non-polymorphic HLA Class Ib molecules with a focus on HLA-F and HLA-G molecules at the time of implantation, including the interaction with uterine immune cells through the specific receptors immunoglobulin-like transcript 2 (ILT2), ILT4 and a number of killer cell immunoglobulin-like receptors (KIRs), and the importance of HLA-F and HLA-G genetic variation that influences fertility and time-to-pregnancy. Drawing on recent advances in basic and clinical studies, we performed a narrative review of the scientific literature to provide a timely update on the role of HLA Class Ib in embryo implantation, fertility and infertility. Pertinent studies were searched in PubMed/Medline using relevant key words. Both HLA-F and HLA-G interact with inhibitory or activating ILT2 or ILT4 receptors and KIRs on uterine immune cells, especially uterine natural killer (NK) cells that are highly abundant in the mid-secretory endometrium and in early pregnancy. The binding of HLA-G to ILT2 stimulates the secretion of growth-promoting factors from decidual NK cells. However, functional aspects of a HLA-F-receptor interaction remain to be clarified. Recent studies indicate that HLA-F and HLA-G are expressed in mid-secretory endometrium and HLA-G is expressed in the blastocyst. HLA-F fluctuates during the menstrual cycle with high levels during the implantation window. The level of HLA-F protein expression correlates with the number of CD56-positive NK cells in the mid-secretory endometrium. HLA-F and HLA-G gene polymorphisms, including a single nucleotide polymorphism (SNP) in a progesterone-responsive element, are associated with time-to-pregnancy. Depending on the SNP genotype, the effect of progesterone varies resulting in differences in HLA-F expression and thereby the interaction with receptors on the uterine NK cells. Studies suggest that the expression of HLA-G and HLA-F, both by the embryonic-derived trophoblast cells and by cells in the endometrium and decidua, and the interaction between HLA-G and HLA-F with specific receptors on uterine immune cells, stimulate and facilitate embryo implantation and placentation by secretion of growth factors, cytokines and angiogenic factors. A detailed understanding of the molecular mechanisms controlling the expression of HLA-F and HLA-G periconceptionally and in early pregnancy may improve the success of ART and holds promise for further insight into pathophysiological aspects of certain pregnancy complications.

A Carbon/Oxygen-dominated Atmosphere Days after Explosion for the “Super-Chandrasekhar” Type Ia SN 2020esm

Abstract Seeing pristine material from the donor star in a type Ia supernova (SN Ia) explosion can reveal the nature of the binary system. In this paper, we present photometric and spectroscopic observations of SN 2020esm, one of the best-studied SNe of the class of “super-Chandrasekhar” SNe Ia (SC SNe Ia), with data obtained −12 to +360 days relative to peak brightness, obtained from a variety of ground- and space-based telescopes. Initially misclassified as a type II supernova, SN 2020esm peaked at M B = −19.9 mag, declined slowly (Δm 15(B) = 0.92 mag), and had particularly blue UV and optical colors at early times. Photometrically and spectroscopically, SN 2020esm evolved similarly to other SC SNe Ia, showing the usual low ejecta velocities, weak intermediate-mass elements, and the enhanced fading at late times, but its early spectra are unique. Our first few spectra (corresponding to a phase of ≳10 days before peak) reveal a nearly pure carbon/oxygen atmosphere during the first days after explosion. This composition can only be produced by pristine material, relatively unaffected by nuclear burning. The lack of H and He may further indicate that SN 2020esm is the outcome of the merger of two carbon/oxygen white dwarfs. Modeling its bolometric light curve, we find an 56Ni mass of 1.23 − 0.14 + 0.14 M ☉ and an ejecta mass of 1.75 − 0.20 + 0.32 M ☉, in excess of the Chandrasekhar mass. Finally, we discuss possible progenitor systems and explosion mechanisms of SN 2020esm and, in general, the SC SNe Ia class.

Abstract P5-13-13: PIK3CA mutations co-occurring with copy number gain identify patients with adverse outcome and potentially different treatment sensitivity among hormone receptor positive and HER2 negative metastatic breast cancer

Abstract INTRODUCTION: Somatic mutations of the PIK3CA gene, encoding for the class IA PI3K p110α subunit, are the most common activating mutations in breast cancer (BC), occurring in 30-50% of early and in 28% of metastatic ER+/HER2- disease. We have previously demonstrated that PIK3CA mutations co-occurring with copy number (CN) gain (PIK3CA-mut/gain) are associated with worse outcome in patients with early hormone receptor positive and HER2 negative (HR+/HER2-) BC, including those receiving endocrine therapy (ET). Here we aim to evaluate the prognostic role of PIK3CA-mut/gain in patients with metastatic HR+/HER2- BC treated with chemotherapy, ET alone or in combination with targeted therapies (CDK4/6 inhibitors or everolimus) included in a publicly available dataset of BC. PATIENTS AND METHODS: We accessed genomic, clinical, treatment and outcome data from 1365 patients with HR+/HER2- BC included in the MSK-2018 dataset. Patients treated for distant metastases were selected. PIK3CA status, considering both protein-affecting mutations and CN alterations, was derived from pre-treatment biopsies data. Tumors were classified as: PIK3CA wt and CN neutral (-wt/neut), PIK3CA wt with CN gain (-wt/gain), PIK3CA mutant and CN neutral (-mut/neut), and PIK3CA mutant with CN gain (-mut/gain). Tumors with PIK3CA loss were excluded from the analyses. For each patient and treatment type, only progression free survival (PFS) from the first available line of treatment was analyzed, thus excluding data concerning possible retreatments with the same drug in subsequent lines. Multivariate Cox proportional hazard models were used to assess the association between PIK3CA status and PFS including treatment line and the four categories of PIK3CA as co-variates. RESULTS: The proportion of PIK3CA-mut/gain was 15.4% in the chemotherapy group (n=454), 17.3% in the ET alone group (n= 352), 13.4% in the ET plus CDK4/6 inhibitors group (n= 268) and 10.5% in the ET plus everolimus group (n= 143). As expected, in all groups treatment line was significantly and independently associated with PFS. In the ET alone group, patients whose tumors had gain in PIK3CA CN, with or without co-occurring mutations, were at significantly higher risk of progression compared with PIK3CA-wt/neut (HR 2.2 [1.53-3.2] p<0.001 for PIK3CA -mut/gain; HR 1.5 [1.03-2.2] p= 0.034 for PIK3CA-wt/gain), while PIK3CA-mut/neut status was not significantly associated with progression (HR 1.2 [0.87 − 1.6] p= 0.289). Similar observations, without reaching statistical significance, were also made in the CDK4/6 inhibitors group (HR 1.6 [0.92-2.6] p= 0.099 for PIK3CA-mut/gain; HR 1.6 [0.97-2.5] p= 0.068 for PIK3CA-wt/gain) and in the chemotherapy group (HR 1.4 [0.98-2] p= 0.063 for PIK3CA-mut/gain; 1.2 [0.89-1.6] p= 0.223 for PIK3CA-wt/gain). On the other hand, in patients treated with ET plus everolimus, while there was a borderline significant increased risk of progression for patients with PIK3CA-wt/gain tumors (HR 1.8 [1.00 − 3.3] p= 0.051) and for those with PIK3CA-mut/neut (HR 1.6 [0.98-2.5) p= 0.06), this was not observed in patients with PIK3CA-mut/gain tumors (HR 1.1 [0.5-2.2] p=0.89), potentially suggesting a treatment benefit. CONCLUSIONS: Our data suggest that patients with metastatic HR+/HER2- BC with tumors with PIK3CA-mut/gain have poor outcome. These data are in line with our previous report in patients with early BC. Further studies are warranted to understand if patients with PIK3CA-mut/gain tumors might benefit from the combination of ET and everolimus. Citation Format: Ilenia Migliaccio, Marta Paoli, Emanuela Risi, Chiara Biagioni, Laura Biganzoli, Matteo Benelli, Luca Malorni. PIK3CA mutations co-occurring with copy number gain identify patients with adverse outcome and potentially different treatment sensitivity among hormone receptor positive and HER2 negative metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-13.