Discovery of Orally Bioavailable Phthalazinone Analogues as an ENPP1 Inhibitor for STING-Mediated Cancer Immunotherapy.

A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes (STING)-mediated innate immunity has emerged as a novel therapeutic approach in cancer therapy. 2',3'-Cyclic GMP-AMP (cGAMP) is a natural STING agonist; however, cGAMP is subjected to endogenous degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). To improve the ICI response rate, we developed 29f, a novel ENPP1 inhibitor with phthalazin-1(2H)-one as the core scaffold. 29f inhibited the cGAMP hydrolysis by ENPP1 in vitro (IC50 = 68 nM) and enhanced the STING-mediated type I interferon response in both immune and tumor cells. 29f demonstrated excellent metabolic stability and bioavailability (F = 65%). Orally administered 29f promoted tumor growth inhibition in a CT26 syngeneic model and increased the anti-PD-L1 response. Furthermore, 29f-induced immunological memory prevented the tumor relapse against tumor rechallenge, suggesting the promising therapeutic potential of 29f.

Clinical features at the time of non-hysteroscopic myomectomy before pregnancy, which affect adverse pregnancy outcomes: a retrospective cohort study.

BACKGROUND: To investigate the association of clinical characteristics at the time of non-hysteroscopic myomectomy before pregnancy and adverse obstetric outcomes in the next pregnancy. METHODS: In this retrospective cohort study, we identified 248 women who underwent abdominal or laparoscopic myomectomy for intramural (IM) and/or subserosal (SS) uterine myomas in Bundang CHA Medical Center before pregnancy and delivered at the same hospital between 2010 and 2020. The association between clinical characteristics at the time of myomectomy and subsequent obstetric outcomes was analyzed using the Chi-square test, the Student t-test or one-way ANOVA, and multivariable analysis. RESULTS: There was one case of uterine rupture. The gestational age at delivery was 37.7 ± 2.4 weeks. There were 2 (0.8%) cases of fetal loss before 23 weeks, but there were no cases of perinatal death. The risk of transfusion during or after delivery was higher in the group in which multiple myomas were removed compared to the group in which only one was removed (aOR = 2.41, 95% CI [1.20-4.86], p = 0.014). The risk of neonatal composite morbidity was higher in the group in which myomas including the IM type were removed, than in the group in which only SS myomas were removed (aOR = 14.29, 95% CI [1.82-99.57], p = 0.012). Although not statistically significant, the group in which the sum of the diameters of the three largest myomas was greater than 15 cm showed a higher frequency of preterm birth (19.3% vs. 10.1%, p = 0.001) and lower birth weight (2901 ± 625 g vs. 3063 ± 576 g, p = 0.001) compared to the group with diameters less than 15 cm. Placenta accreta/increta (7.9% vs. 3.8%, p = 0.043) and lower placental weight (646 ± 170 g vs. 750 ± 232 g, p = 0.034) were more common in patients with an interval between myomectomy and pregnancy of less than 12 months compared to more than 12 months. CONCLUSIONS: To our knowledge, this is the first study to investigate the association between clinical features at the time of myomectomy before pregnancy and various adverse obstetric and perinatal outcomes. If the removed myomas are multiple, IM, large, or the interval between myomectomy and pregnancy is short, the risk of obstetric and neonatal complications may increase.

Discovery of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives as novel ENPP1 inhibitors.

Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) negatively regulates the anti-cancer Stimulator of Interferon Genes (STING) pathway. We discovered that 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives possessed inhibitory activities on ENPP1. A structure-activity relationship (SAR) study led to the identification of 46 and 23 as potent ENPP1 inhibitors. Also, compounds 46 and 23 possessed high microsomal stabilities in human, rat, and mouse liver microsome. Additionally, CYPs (1A2, 2C9, 2C19, 2D6, and 3A4) were not inhibited by 46 and 23. Molecular dynamics simulations provided an insight of binding modes between ENPP1 and compounds (46 and 23).

Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails.

Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor 7a potently inhibited Lck kinase with great selectivity (IC50 of 23.0 nM). It was found that 7a and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that 7a inhibited Lck activation in Jurkat T cells. Moreover, 7a was found to alleviate clinical symptoms in DSS-induced colitis mice. This study provides a novel insight into the design of selective type II kinase inhibitors by adopting chiral peptidomimetic moieties on the tail region.

Potential of Tissue-Engineered and Artificial Dermis Grafts for Fingertip Reconstruction.

BACKGROUND: Management of skin and soft-tissue defects of the fingertips is functionally and aesthetically important, but controversial, especially when bones are exposed. Recent advances in wound healing technology allow the use of cells or biological dermis. The authors studied the clinical efficacy of tissue-engineered dermis grafts and artificial dermis grafts versus immediate reconstructive procedures, such as the reverse digital artery island flap, in treating bone-exposed fingertip defects. METHODS: One hundred eighty-two patients with bone-exposed fingertip defects treated with tissue-engineered dermis grafts (n = 71), artificial dermis grafts (n = 23), or reverse digital artery island flaps (n = 88) were included in this retrospective cohort study. Surgical time, duration of hospitalization, total cost, success rate, healing time, sensory recovery, range of motion, scar quality, and patient satisfaction were compared. RESULTS: No tissue-engineered or artificial dermis graft exhibited graft rejection or failure, whereas there was one partial loss and one total loss after reverse digital artery island flap surgery. Tissue-engineered dermis grafts were superior in scar quality, and artificial dermis grafts had shorter surgical times and lower surgical costs; both groups demonstrated superior results in postoperative range of motion and sensory recovery in two-point discrimination tests and shorter hospitalization, compared with the reverse digital artery island flap group. The reverse digital artery island flap had shorter complete closure time and less postoperative tingling sensation. There were no differences in overall patient satisfaction among the groups. CONCLUSIONS: Tissue-engineered and artificial dermis grafts may be promising alternatives for fingertip reconstruction. In particular, tissue-engineered dermis grafts may deliver superior functional results, including recovery of sensory discomfort and aesthetic results in terms of scar quality over artificial dermis grafts. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Preoperative Nasal Swab Culture: Is It Beneficial in Preventing Postoperative Infection in Complicated Septorhinoplasty?

BACKGROUND: Surgical-site infection following complicated septorhinoplasty may result in serious complications. Therefore, efforts to prevent surgical-site infections after complicated septorhinoplasty are important. The purpose of this study was to analyze the microbiological profile of preoperative nasal swab cultures and to evaluate the effect of antibiotic prophylaxis and topical antibiotic decolonization according to the antibiotic sensitivity results of surgical-site infections in complicated septorhinoplasty. METHODS: This 10-year cohort study included the data on 437 consecutive patients who underwent complicated septorhinoplasty. The patients were categorized into three cohorts based on the time of preoperative nasal swab culture collection. Patients in cohort 1 did not undergo nasal swab cultures and received empirical antibiotics. Patients in cohort 2 underwent only one preoperative nasal swab culture and received microorganism-sensitive antibiotics. Patients in cohort 3 underwent repeated nasal swab cultures. The antibiotics were changed when microorganisms resistant to the empirical antibiotics were isolated. Microbiological data and the rates of surgical-site infection and inflammation were compared among the three cohorts. RESULTS: Methicillin-sensitive Staphylococcus aureus was the most commonly isolated microorganism. In cohort 1, two (5 percent) and two (5 percent) patients experienced surgical-site infections and inflammation, respectively. In cohort 2, two (3 percent) and three (4 percent) patients experienced surgical-site infections and inflammation, respectively. In cohort 3, one (0.3 percent) and one (0.3 percent) patient experienced surgical-site infection and inflammation, respectively. CONCLUSION: The present study demonstrated that preoperative screening using repeated nasal swab cultures, followed by appropriate antibiotic prophylaxis and topical antibiotic decolonization, may reduce surgical-site infection in complicated septorhinoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Effects of Granulocyte Macrophage Colony-Stimulating Factor Inhibition on the Skin/Nerve Cell Model In Vitro.

The present study is based on the concept of neuro-aging and how it may affect surrounding skin cells. It has been shown that many factors play a significant role in skin homeostasis by interfering with various cytokines, either through activation or inhibition. Granulocyte macrophage colony-stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine, and our previous study has shown its effects on neuronal senescence after ultraviolet (UV) irradiation of skin cells. Following our previous work, this study was performed to investigate the neuroprotective effects of a GM-CSF antagonist, and how it may play an essential role in mediating anti-senescence and anti-inflammatory effects in the keratinocyte/nerve aging model. When human blastoma cells (SH-SY5Y) were treated with 10 ng/ml of GM-CSF, the levels of regulatory RNAs associated with aging, such as matrix metalloproteinase-9 (MMP9), nuclear factor NF-kappa-B p50 subunit (NFKB), inducible nitric oxide synthase (iNOS), and interleukin 1 beta (IL-1ß) increased, whereas GM-CSF inhibition caused their expression to decrease. A decrease in the antioxidant, glutathione (GSH) was observed after SH-SY5Y cells were treated with GM-CSF. This study confirms that this GM-CSF antagonist may play an important role in neural senescence, where inhibition may be a new target in the skin/nerve aging model.

Septorhinoplasty for Destructed Septal L-Strut in Patients with Previously Applied Porous High-Density Polyethylene Implants (Medpor®).

BACKGROUND: Porous high-density polyethylene implants (Medpor®) have been extensively used for septal extension grafts in Asian rhinoplasty. However, studies on the long-term complications associated with Medpor® have not been reported. Therefore, the purpose of this study was to evaluate the long-term complications of septal extension grafts using Medpor® and present a reconstructive strategy for destructed septal L-struts. METHODS: We conducted a 12-year retrospective medical chart review of 428 patients who visited our center for septorhinoplasty. Among 428 patients, 43 patients had Medpor® for septal extension grafts previously applied at other clinics. The quadrangular cartilage was devoid or destructed in the area where Medpor® was previously applied. Therefore, all patients underwent secondary septorhinoplasty using autogenous cartilage grafts. Patient outcome was assessed to evaluate satisfaction, hardness of nasal tip, functional nasal obstruction symptom evaluation (NOSE) scores, and pain scores. Anthropometric analyses were carried out with patients' photographs. Postoperative complications were also evaluated. RESULTS: After septal L-strut reconstruction, 87% of patients were satisfied with their aesthetic results. Hardness of nasal tip, NOSE scores, and pain scores also improved after reconstruction. Anthropometric analyses demonstrated that increased nasal length and decreased columellar-labial angle were achieved in patients with short nose deformities. No postoperative complications related to the reconstruction were recorded for any patient. CONCLUSIONS: The devastated destruction of nasal support lines was found after the use of Medpor® for septorhinoplasty. Therefore, the use of Medpor® should be reduced. Autogenous cartilage grafts are the last resort for reconstruction of destructed septal L-struts. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The Ancient Phosphatidylinositol 3-Kinase Signaling System Is a Master Regulator of Energy and Carbon Metabolism in Algae.

Algae undergo a complete metabolic transformation under stress by arresting cell growth, inducing autophagy and hyper-accumulating biofuel precursors such as triacylglycerols and starch. However, the regulatory mechanisms behind this stress-induced transformation are still unclear. Here, we use biochemical, mutational, and "omics" approaches to demonstrate that PI3K signaling mediates the homeostasis of energy molecules and influences carbon metabolism in algae. In Chlamydomonas reinhardtii, the inhibition and knockdown (KD) of algal class III PI3K led to significantly decreased cell growth, altered cell morphology, and higher lipid and starch contents. Lipid profiling of wild-type and PI3K KD lines showed significantly reduced membrane lipid breakdown under nitrogen starvation (-N) in the KD. RNA-seq and network analyses showed that under -N conditions, the KD line carried out lipogenesis rather than lipid hydrolysis by initiating de novo fatty acid biosynthesis, which was supported by tricarboxylic acid cycle down-regulation and via acetyl-CoA synthesis from glycolysis. Remarkably, autophagic responses did not have primacy over inositide signaling in algae, unlike in mammals and vascular plants. The mutant displayed a fundamental shift in intracellular energy flux, analogous to that in tumor cells. The high free fatty acid levels and reduced mitochondrial ATP generation led to decreased cell viability. These results indicate that the PI3K signal transduction pathway is the metabolic gatekeeper restraining biofuel yields, thus maintaining fitness and viability under stress in algae. This study demonstrates the existence of homeostasis between starch and lipid synthesis controlled by lipid signaling in algae and expands our understanding of such processes, with biotechnological and evolutionary implications.

The effectiveness and safety of nonsurgical integrative interventions for symptomatic lumbar spinal spondylolisthesis: A randomized controlled multinational, multicenter trial protocol.

BACKGROUND: Surgery is generally accepted as the main therapeutic option for symptomatic lumbar spondylolisthesis. However, new nonsurgical therapeutic options need to be explored for this population. OBJECTIVES: The objective of this study is to assess the effectiveness and safety of a 5-week Mokhuri treatment program compared with conventional nonsurgical treatments for symptomatic lumbar spondylolisthesis. METHODS: This is a study protocol for a multinational, multicenter clinical randomized controlled trial comparing the effectiveness and safety of 5 weeks of nonsurgical integrative treatments (a Mokhuri treatment program consisting of Chuna, acupuncture, and patient education) with nonsurgical conventional treatments (drugs for pain relief, epidural steroid injections, and physical therapy). Clinical outcomes including visual analogue scale (VAS) scores ranging from 0 to 100 for low back pain and leg pain, EQ-5D scores, Oswestry disability index (ODI) scores, Roland-Morris Disability Questionnaire (RMDQ) scores, Zurich Claudication Questionnaire (ZCQ) scores, walking duration and distance without leg pain, and a 5-minute treadmill test, and the ratio between the actual duration of participation and the originally scheduled duration in each group, the presence of any additional spondylolisthesis treatments, the types of concomitant treatments during the follow-up period, and adverse events (AEs) will be assessed at 7 weeks, 18 weeks, 30 weeks, 54 weeks, and 102 weeks after the end of the treatments. CONCLUSION AND DISCUSSION: The results of this study will provide clinical evidence on nonsurgical integrative interventions for patients with symptomatic lumbar spondylolisthesis. CLINICAL TRIAL REGISTRY:: clinicaltrials.gov (NCT03107468).

Exercise improves the effects of testosterone replacement therapy and the durability of response after cessation of treatment: a pilot randomized controlled trial.

The effects of the combination of exercise and TRT on symptoms of late-onset hypogonadism (LOH) and the durability of response after cessation of TRT were investigated. A total of fifty patients with erectile dysfunction (ED) who had a sedentary lifestyle and low serum total testosterone (T) levels were enrolled and followed for 20 weeks. Patients were randomly divided into two groups; all of them received T gel for 12 weeks and it was discontinued for 8 weeks. Patients assigned to Group II were offered a supervised exercise program for 20 weeks. Measurement of serological testing was performed and self-assessment questionnaires and Global Assessment Question (GAQ) were asked. Baseline characteristics and the initial symptom scores showed no significant difference between the two groups. Serum total T levels and the symptom scores were increased at 12 weeks in both groups, and Group II showed better results with statistical significance. There was a decrease in T levels and worsening of symptom scores at week 20 compared to week 12 in both groups, and Group II showed better results with statistical significance. On the GAQ, Group II showed higher ratio of "yes" at week 12 and the same tendency was sustained at week 20 with significant difference between two groups. The combination of exercise and TRT showed significant improvements in serum T levels and LOH symptoms compared to TRT alone. In addition, these improvements were maintained in the combination group with continuous exercise, even after cessation of TRT.

Predictive factors associated with failure of nonoperative treatment of superior labrum anterior-posterior tears.

BACKGROUND: Uncertainty remains in the natural course of superior labrum anterior-posterior (SLAP) tears treated conservatively with rehabilitation and activity modification. Our purpose was to evaluate clinical outcomes after nonoperative treatment of type II SLAP tear in young active patients and to identify factors related to negative outcomes. METHODS: We retrospectively reviewed 63 patients who initially underwent nonoperative treatment for isolated type II SLAP tear. Assessments were made at baseline and at 6 months, and telephone survey was used to evaluate the final outcome. All included patients underwent a consistent nonoperative treatment protocol, and patient-specific data on the outcome were assessed. Failure was defined as abandonment of nonoperative management for surgery at any time points, <20-point improvement in American Shoulder and Elbow Surgeons score at final follow-up, or inability to return to activities. RESULTS: At the average follow-up of 21 months, pain relief and function improved significantly (American Shoulder and Elbow Surgeons score, 54.2-86.4; Visual Analog Scale score, 4.6-1.7; P < .05) in 45 patients (71.4%) with successful nonoperative treatment. Eighteen patients (28.5%) were either dissatisfied with treatment or had arthroscopic surgery and were considered a failure group. Multivariate analysis showed that failure of nonoperative treatment is strongly linked with history of trauma, positive compression-rotation test result, and participation in overhead activities (P < .05). CONCLUSIONS: An initial trial of nonoperative management may be considered in young active patients with isolated SLAP tear. Patients with history of trauma, mechanical symptoms, and demand for overhead activities are less likely to succeed.

Clinical and radiologic outcomes after meniscus allograft transplantation at 1-year and 4-year follow-up.

PURPOSE: To assess the clinical and radiologic outcomes of meniscus allograft transplantation (MAT) with serial evaluation at 1 year and at 4 years. METHODS: Among 151 patients who received MAT between March 2006 and June 2009, we prospectively recruited the patients who had undergone clinical and radiologic examinations at 1 year after the operation. The Lysholm score, International Knee Documentation Committee score, and Knee Society Score were determined. Plain radiography was used for evaluation of osteoarthritis, and magnetic resonance imaging (MRI) was used to assess the cartilage status and meniscal extrusion. RESULTS: Thirty-nine patients with a mean age of 40 ± 9 years were recruited. The first visit was conducted at a mean of 13.6 months (range, 11 to 17 months) postoperatively, and the last visit was conducted at a mean of 50.4 months (range, 48 to 72 months) postoperatively. Of the patients, 29 were men. The lateral side was involved in 27 patients. The Lysholm knee score increased to a median value of 89 (range, 75 to 100) at the first visit and 88 (range, 76 to 100) at the second visit from a preoperative median value of 79 (range, 37 to 99), which was statistically significant according to the Kruskal-Wallis test. According to the Kellgren-Lawrence grade based on anteroposterior radiographs, 21 patients (54%) showed no arthrosis progression and the overall status of arthrosis on anteroposterior radiographs was significantly changed (P < .001). On MRI, 25 patients (64%) showed no cartilage status change and the overall status was not changed significantly (P = .178). The meniscal extrusion extent was 4.2 ± 0.4 mm at the first visit and 4.2 ± 0.6 mm at the second visit (P = .678), and the relative percentage of extrusion was 0.44 ± 0.16 and 0.51 ± 0.21, respectively (P = .059). The subgroup in which arthrosis had progressed on MRI showed a larger amount of change in the relative percentage of extrusion (P = .023). No correlation was observed between meniscal extrusion and various outcomes. CONCLUSIONS: Repeat assessment at 4 years showed that MAT showed improvement in knee function, but it had decreased over time. Considerable meniscal extrusion was observed, but it did not increase during follow-up and did not show any correlation with other outcomes. Extrusion progression showed significant correlation with arthrosis progression. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Evaluation of image quality and radiation dose by adaptive statistical iterative reconstruction technique level for chest CT examination.

The purpose of this research is to determine the adaptive statistical iterative reconstruction (ASIR) level that enables optimal image quality and dose reduction in the chest computed tomography (CT) protocol with ASIR. A chest phantom with 0-50 % ASIR levels was scanned and then noise power spectrum (NPS), signal and noise and the degree of distortion of peak signal-to-noise ratio (PSNR) and the root-mean-square error (RMSE) were measured. In addition, the objectivity of the experiment was measured using the American College of Radiology (ACR) phantom. Moreover, on a qualitative basis, five lesions' resolution, latitude and distortion degree of chest phantom and their compiled statistics were evaluated. The NPS value decreased as the frequency increased. The lowest noise and deviation were at the 20 % ASIR level, mean 126.15 ± 22.21. As a result of the degree of distortion, signal-to-noise ratio and PSNR at 20 % ASIR level were at the highest value as 31.0 and 41.52. However, maximum absolute error and RMSE showed the lowest deviation value as 11.2 and 16. In the ACR phantom study, all ASIR levels were within acceptable allowance of guidelines. The 20 % ASIR level performed best in qualitative evaluation at five lesions of chest phantom as resolution score 4.3, latitude 3.47 and the degree of distortion 4.25. The 20 % ASIR level was proved to be the best in all experiments, noise, distortion evaluation using ImageJ and qualitative evaluation of five lesions of a chest phantom. Therefore, optimal images as well as reduce radiation dose would be acquired when 20 % ASIR level in thoracic CT is applied.

Posterolateral corner anatomy and its anatomical reconstruction with single fibula and double femoral sling method: anatomical study and surgical technique.

This paper reports a novel method for reconstructing the posterolateral structures [lateral collateral ligament (LCL), popliteus tendon, popliteofibular ligament] based on an anatomical study of a cadaveric dissection. The popliteus tendon was found to always be attached to the anterior-inferior portion of the femoral attachment site of the LCL, and the average distance from the origin of the popliteal tendon in the femoral side to that of the LCL was 18.5 mm (17-20). The insertion site of the LCL in the fibular side was located anterior-inferior-superficially and the popliteofibular ligament was inserted into the posterior-superior-deep portion around the styloid process. Two femoral tunnels and one fibular head tunnel were made at the proximal and distal portion of the anatomical insertion sites.

Initial dose cascade of TTS fentanyl with proper adjuvant medications in cancer pain.

According to the three step-ladder analgesics in patients with cancer pain, adjuvant drugs are required for pain relief according to the pain character and also to reduce side effects of opioids. Pain clinicians sometimes want to decide to jump directly from naive and mild opioid to transdermal therapeutic system (TTS) fentanyl with less side effects. We investigated the safety, efficacy, and satisfaction of the patients of TTS fentanyl converting from opioid-naive and mild-opioid with adjuvant drug medications in related to dose cascade of TTS fentanyl. Both opioid-naive (n=3) and opioid-using (n=34) patients started with TTS fentanyl in the lowest available delivery rate (25 microg/hr) with rescue medication. A numeric rating scale (NRS, from 0=no pain to 10=worst pain imaginable), satisfaction of the patients with the transdermal therapy and side effects were recorded everyday during 29 days. Average reductions of NRS scores were 1.79 and 2.77, and the mean doses were 35.14 and 44.12 microg/hr on the 15th and 29th day, respectively. Reported level of satisfaction with the transdermal patch and generalized pain management were 'completely satisfied' and 'satisfied'. Frequent side effects were nausea, vomiting, and constipation. In conclusion, initial application of TTS fentanyl with proper adjuvant medications is effective, safe, and well tolerated.