SOX7 deficiency causes ventricular septal defects through its effects on endocardial-to-mesenchymal transition and the expression of Wnt4 and Bmp2.

SOX7 is a transcription factor-encoding gene located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with ventricular septal defects (VSDs). We have previously shown that Sox7-/- embryos die of heart failure around E11.5. Here, we demonstrate that these embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. Ablation of Sox7 in the endocardium also resulted in hypocellular endocardial cushions, and we observed VSDs in rare E15.5 Sox7flox/-;Tie2-Cre and Sox7flox/flox;Tie2-Cre embryos that survived to E15.5. In atrioventricular explant studies, we showed that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). RNA-seq studies performed on E9.5 Sox7-/- heart tubes revealed severely reduced Wnt4 transcript levels. Wnt4 is expressed in the endocardium and promotes EndMT by acting in a paracrine manner to increase the expression of Bmp2 in the myocardium. Both WNT4 and BMP2 have been previously implicated in the development of VSDs in individuals with 46,XX sex reversal with dysgenesis of kidney, adrenals and lungs (SERKAL) syndrome and in individuals with short stature, facial dysmorphism and skeletal anomalies with or without cardiac anomalies 1 (SSFSC1) syndrome, respectively. We now show that Sox7 and Wnt4 interact genetically in the development of VSDs through their additive effects on endocardial cushion development with Sox7+/-;Wnt4+/- double heterozygous embryos having hypocellular endocardial cushions and perimembranous and muscular VSDs not seen in their Sox7+/- and Wnt4+/- littermates. These results provide additional evidence that SOX7, WNT4 and BMP2 function in the same pathway during mammalian septal development and that their deficiency can contribute to the development of VSDs in humans.

Tailoring Single-Electron Emission Distributions in the Time-Energy Phase Space.

The precise characterization and control of single-electron wave functions emitted from a single-electron source are essential for advancing electron quantum optics. Here, we introduce a method for tailoring a single-electron emission distribution using energy filtering, enabling selective control of the distribution under various energy barrier conditions of the filter. The tailored electron is studied by reconstructing its Wigner distribution in the time-energy phase space using the continuous-variable tomography method. Our results reveal that the filtering cuts the portion of the distribution below the energy-barrier height of the filter in the time-energy space. While the filtering is demonstrated in a classical regime of the emitted electrons, we expect that this study significantly contributes to the design and implementation of advanced experiments toward quantum information processing based on single electrons.

Time Window for Induced Hypertension in Acute Small Vessel Occlusive Stroke With Early Neurological Deterioration.

BACKGROUND: Therapeutic-induced hypertension treatment (iHTN) is helpful for alleviating early neurological deterioration (END) in acute small vessel occlusive stroke. We examined the time parameters related to iHTN effectiveness in these patients. METHODS: We retrospectively reviewed patients with acute small vessel occlusive stroke who underwent iHTN for END, defined as an increase of ≥2 points in total National Institutes of Health Stroke Scale (NIHSS) score or ≥1 point in motor items of NIHSS. The primary outcome was an early neurological improvement (ENI; a decrease of ≥2 points in total NIHSS score or ≥1 point in motor items of NIHSS), and the secondary outcome was any neurological improvement (a decrease of ≥1 point in the total NIHSS score). We conducted a multivariable logistic regression analysis, adjusting for demographics, risk factors, baseline clinical status, and intervention-related variables. We also generated a restricted cubic spline curve for the END-to-iHTN time cutoff. RESULTS: Among the 1062 patients with small vessel occlusive stroke screened between 2017 and 2021, 136 patients who received iHTN within 24 hours from END were included. The mean age was 65.1 (±12.0) years, and 61.0% were male. Sixty-five (47.8%) patients showed ENI and 77 (56.6%) patients showed any neurological improvement. END-to-iHTN time was significantly shorter in patients with ENI (150 [49-322] versus 290 [97-545] minutes; P=0.018) or any neurological improvement (150 [50-315] versus 300 [130-573] minutes; P=0.002). A 10-minute increase in the time between END and iHTN decreased the odds of achieving ENI (odds ratio, 0.984 [95% CI, 0.970-0.997]; P=0.019) or any neurological improvement (odds ratio, 0.978 [95% CI, 0.964-0.992]; P=0.002). The restricted cubic spline curve showed that the odds ratio of ENI reached its minimum at ≈3 hours. CONCLUSIONS: Among patients with small vessel occlusive stroke with END, a shorter interval between END and the initiation of iHTN was associated with increased odds of achieving neurological improvement. The efficacy of iHTN may be limited to induction within the first 3 hours of END.

The Efficacy and Safety of Radiation-Free Retrograde Intrarenal Surgery: A Prospective Multicenter-Based, Randomized, Controlled Trial.

PURPOSE: Fluoroscopy is usually required during retrograde intrarenal surgery (RIRS). Although fluoroscopy is considered necessary for effective and safe RIRS, there is growing awareness regarding radiation exposure risk to patients and surgeons. We conducted a multicenter-based, randomized, controlled trial to compare the safety and effectiveness of radiation-free (RF) RIRS with radiation-usage (RU) RIRS for kidney stone management. MATERIALS AND METHODS: From August 2020 to April 2022, patients with a unilateral kidney stone (≤20 mm) eligible for RIRS were prospectively enrolled in 5 tertiary medical centers after randomization and divided into the RF and RU groups. RIRS was performed using a flexible ureteroscope with a holmium:YAG laser. The primary end point of this study was the success rate, defined as complete stone-free or residual fragments with asymptomatic kidney stones ≤ 3 mm. The secondary end point of this study was ascertaining the safety of RF RIRS. The success rates were analyzed using a noninferiority test. RESULTS: Of the 140 consecutive randomized participants, 128 patients completed this study (RF: 63; RU: 65). The success rates (78% vs 80%, P = .8) were not significantly different between the groups. The rate of high-grade (grade 2-4) ureter injury was not significantly higher in the RF group compared to the RU group (RF = 3 [4.8%] vs RU = 2 [3.1%], P = .6). In RF RIRS, the success rate was noninferior compared to RU RIRS (the difference was 2.2% [95% CI, 0.16-0.12]). CONCLUSIONS: This study demonstrated that the surgical outcomes of RF RIRS were noninferior to RU RIRS.

PWWP2B promotes DNA end resection and homologous recombination.

Genome instability is one of the leading causes of gastric cancers. However, the mutational landscape of driver genes in gastric cancer is poorly understood. Here, we investigate somatic mutations in 25 Korean gastric adenocarcinoma patients using whole-exome sequencing and show that PWWP2B is one of the most frequently mutated genes. PWWP2B mutation correlates with lower cancer patient survival. We find that PWWP2B has a role in DNA double-strand break repair. As a nuclear protein, PWWP2B moves to sites of DNA damage through its interaction with UHRF1. Depletion of PWWP2B enhances cellular sensitivity to ionizing radiation (IR) and impairs IR-induced foci formation of RAD51. PWWP2B interacts with MRE11 and participates in homologous recombination via promoting DNA end-resection. Taken together, our data show that PWWP2B facilitates the recruitment of DNA repair machinery to sites of DNA damage and promotes HR-mediated DNA double-strand break repair. Impaired PWWP2B function might thus cause genome instability and promote gastric cancer development.

Association between Rapid Ventricular Response and Stroke Outcomes in Atrial Fibrillation-Related Cardiac Embolic Stroke.

INTRODUCTION: Patients with atrial fibrillation-related stroke (AF-stroke) are prone to developing rapid ventricular response (RVR). We investigated whether RVR is associated with initial stroke severity, early neurological deterioration (END) and poor outcome at 3 months. METHODS: We reviewed patients who had AF-stroke between January 2017 and March 2022. RVR was defined as having heart rate >100 beats per minute on initial electrocardiogram. Neurological deficit was evaluated with National Institutes of Health Stroke Scale (NIHSS) score at admission. END was defined as increase of ≥2 in total NIHSS score or ≥1 in motor NIHSS score within first 72 h. Functional outcome was score on modified Rankin Scale at 3 months. Mediation analysis was performed to examine potential causal chain in which initial stroke severity may mediate relationship between RVR and functional outcome. RESULTS: We studied 568 AF-stroke patients, among whom 86 (15.1%) had RVR. Patients with RVR had higher initial NIHSS score (p < 0.001) and poor outcome at 3 months (p = 0.004) than those without RVR. The presence of RVR [adjusted odds ratio (aOR) = 2.13; p = 0.013] was associated with initial stroke severity, but not with END and functional outcome. Otherwise, initial stroke severity [aOR = 1.27; p = <0.001] was significantly associated with functional outcome. Initial stroke severity as a mediator explained 58% of relationship between RVR and poor outcome at 3 months. CONCLUSION: In patients with AF-stroke, RVR was independently associated with initial stroke severity but not with END and functional outcome. Initial stroke severity mediated considerable proportion of association between RVR and functional outcome.

Association between renal insufficiency and lesion characteristics of posterior reversible encephalopathy syndrome.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is characterized by cerebral blood flow dysregulation and the blood-brain barrier (BBB) disruption. While renal insufficiency has been considered a factor in BBB fragility, the relationship between renal insufficiency and the PRES lesions volume remains unclear. METHODS: This observational study was performed retrospectively. PRES patients were categorized into two groups with renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2 on the day of symptom occurrence. Lesion volume was measured using fluid-attenuated inversion recovery (FLAIR) imaging, and the brain was divided into nine regions. The volume of the parietal-occipital-temporal lobe was considered typical, while the other six regions were labeled as atypical. RESULTS: The study included 200 patients, of whom 94 (47%) had renal insufficiency. Patients with renal insufficiency had a larger lesion volume (144.7 ± 125.2 cc) compared to those without renal insufficiency (110.5 ± 93.2 cc; p = 0.032); particularly in the atypical lesions volume (49.2 ± 65.0 vs. 29.2 ± 44.3 cc; p = 0.013). However, there was no difference in the reversibility of the lesions (35.2 ± 67.5 vs. 18.8 ± 33.4 cc; p = 0.129). Multiple regression analysis revealed that decreases in eGFR (ß = -0.34, 95% CI -0.62-0.05, p = 0.020) were positively associated with total lesion volume. CONCLUSION: Our findings suggest that PRES patients with renal insufficiency experience more severe lesion volumes, likely due to the atypical brain regions involvement. The lesions involving atypical regions may have a similar pathophysiology to typical lesions, as the PRES lesions reversibility was found to be similar between individuals with and without renal insufficiency.

Incidence rates of retinal vascular occlusive diseases from 2011 to 2020 in South Korea: a nationwide cohort study.

BACKGROUND: Retinal vascular occlusions, including retinal vein occlusion and retinal artery occlusion, are common causes of visual impairment. In order to evaluate the national medical burden and help improve ophthalmic health care policy planning, we investigated the incidence of retinal vascular occlusive diseases from 2011 to 2020 in Korea. METHODS: This study is a nationwide population-based retrospective study using data from the Korea national health claim database of the Health Insurance Review and Assessment (HIRA) service. We identified retinal vascular occlusive diseases registered from January 1, 2009, to December 31, 2020, according to the retinal vascular occlusion code (H34) and its sub-codes from international classification of disease, tenth revision diagnosis code. We used data from the entire Korean population based on the 2015 census of the population in Korea to calculate standardized incidence rates. RESULTS: We identified 348,775 individuals (male, 161,673 [46.4%]; female, 187,102 [53.6%]) with incident retinal vascular occlusion (H34), 10,451 individuals (males, 6,329 [60.6%]; females, 4,122 [39.4%]) with incident central retinal artery occlusion (H34.1), and 252,810 individuals (males, 114,717 [45.4%]; females, 138,093 [54.6%]) with incident retinal vein occlusion (H34.8) during the 10-year study period. The weighted mean incidence rate of retinal vascular occlusion was 70.41 (95% CI, 70.18-70.65) cases/100,000 person-years. The weighted mean incidence rate of central retinal artery occlusion was 2.10 (95% CI, 2.06-2.14) cases/100,000 person-years. The weighted mean incidence rate of retinal vein occlusion was 50.99 (95% CI, 50.79-51.19) cases/100,000 person-years. CONCLUSION: The total retinal vascular occlusion and retinal vein occlusion showed a decreasing trend until 2020. However, the central retinal artery occlusion decreased until 2014 and remained stable without a significant further decline until 2020. The incidence of total retinal vascular occlusion and retinal vein occlusion was higher in females than in males, while the incidence of central retinal artery occlusion was higher in males. All retinal vascular occlusive diseases showed an increasing incidence with older age; the peak age incidence was 75-79 years for total retinal vascular occlusion and retinal vein occlusion, and 80-85 years for central retinal artery occlusion.

Reproducibility for carotid wall segmentation using T1-weighted DANTE-SPACE sequence on high-resolution 3-T carotid MRI.

BACKGROUND: T1-weighted (T1W) magnetic resonance imaging (MRI) using the delay alternating with nutation for excitation-sampling perfection with application-optimized contrasts using different flip angle evolution (DANTE-SPACE) is the preferred imaging technique for evaluation of the vessel wall. PURPOSE: To evaluate the intra- and inter-rater reproducibility of carotid wall segmentation on T1W DANTE-SPACE in patients with symptomatic (acute stroke or transient ischemic attack) internal carotid artery (ICA) stenosis. MATERIAL AND METHODS: This prospective study included 25 patients with acute (≤3 months) stroke or transient ischemic attack and 50%-99% stenosis of the ICA. All patients underwent 3.0-T high-resolution carotid MRI. Two radiologists independently performed the manual segmentation of the vessel wall and inner lumen of the bilateral carotid artery on DANTE-SPACE. The intraclass correlation coefficient (ICC), Dice similarity coefficient (DSC), and Hausdorff distance (HD) were calculated. RESULTS: The ICCs for intra-rater reproducibility of carotid wall volume, inner lumen volume, and normalized wall index were 0.965, 0.990, and 0.962, respectively. The ICCs for inter-rater reproducibility of carotid wall volume, inner lumen, and normalized wall index were 0.856, 0.981, and 0.904. DSC and HD for intra- and inter-rater reproducibility of carotid wall segmentation were as follows: 0.873 and 0.809 (DSC); and 0.079 and 0.118 (HD), respectively. For evaluation of reproducibility only in the carotid artery with symptomatic stenosis, the ICCs for intra- and inter-rater reproducibility indicated all perfect agreement. CONCLUSION: T1W DANTE-SPACE is a reproducible sequence for evaluation of the carotid wall using carotid MRI in patients with symptomatic ICA stenosis.

Effects of high temperature short time (HTST) pasteurization on milk and whey during commercial whey protein concentrate production.

Two pasteurization steps are often used in the preparation of whey protein concentrate (WPC) before evaporation into a dry product. The Pasteurized Milk Ordinance (PMO) in the United States requires that raw bovine milk be pasteurized using a process that meets minimum heat treatment requirements to achieve reductions in pertinent microorganisms. In addition, WPC produced from USDA-approved plants must comply with CFR Subpart B §58.809, which dictates that all fluid whey used in the manufacture of dry whey products shall be pasteurized before being condensed. These heat treatments are effective at inactivating the most thermally resistant bacterium, such as Coxiella burnetii; however, they can also alter milk proteins-inducing denaturation, aggregation and reduced bioactivity. Though the impact of thermal treatments on whey proteins has been examined, the specific influence of 2 high-temperature-short-time (HTST) pasteurization steps on the retention of proteins in WPC remains unknown. This study aimed to investigate the effect of commercial-scale HTST pasteurization of both raw milk and the resulting sweet whey on the products' overall protein profile. Three distinct batches of raw milk (RM) and corresponding pasteurized milk (PM), the resulting whey (RW) and pasteurized whey (PW) produced at commercial scale were analyzed. Assessments of denaturation were conducted through solubility testing at pH 4.6 and hydrophobicity evaluation via anilinonaphthalene-1-sulfonic acid assay (ANS). Additionally, enzyme-linked immunosorbent assay (ELISA), PAGE (PAGE) and liquid chromatography tandem mass spectroscopy (LC-MS/MS) were employed to compare the retention of key bioactive proteins before and after each HTST pasteurization step. The percentage of soluble whey protein decreased from RM to PM and from RW to PW, but no significant differences were observed via hydrophobicity assay. ELISA revealed a significant reduction in key bioactive proteins, such as lactoferrin, immunoglobulin A and immunoglobulin M, but not immunoglobulin G, after HTST pasteurization of RM and RW. PAGE and LC-MS/MS revealed a significant decrease in the retention of lactoferrin and key milk fat globular membrane proteins, such as xanthine dehydrogenase oxidase/xanthine oxidase, lactadherin and fatty acid binding protein. Additionally, xanthine oxidase activity was significantly reduced after HTST pasteurization of milk and whey. This research helps to identify the limitations of the current processing techniques used in the dairy industry and could lead to innovation in improving the retention of bioactive proteins.

Controlled Bipolar Doping of One-Dimensional van der Waals Nb2Pd3Se8.

Tailoring the electrical properties of one-dimensional (1D) van der Waals (vdW) materials is desirable for their applications toward electronic devices by exploiting their unique characteristics. However, 1D vdW materials have not been extensively investigated for modulation of their electrical properties. Here we control doping levels and types of 1D vdW Nb2Pd3Se8 over a wide energy range by immersion in AuCl3 or ß-nicotinamide adenine dinucleotide (NADH) solutions, respectively. Through spectroscopic analyses and electrical characterizations, we confirm that the charges were effectively transferred to Nb2Pd3Se8, and the dopant concentration was adjusted to the immersion time. Furthermore, we make the axial p-n junction of 1D Nb2Pd3Se8 by a selective area p-doping using the AuCl3 solution, which exhibits rectifying behavior with an Iforward/Ireverse of 81 and an ideality factor of 1.2. Our findings could pave the way to more practical and functional electronic devices based on 1D vdW materials.

Dynamic changes of systemic inflammation response index and systemic immune-inflammation index are associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Delayed cerebral ischemia (DCI) is a factor contributing to poor outcome of aneurysmal subarachnoid hemorrhage (aSAH). Serial inflammatory response is known to affect the occurrence of DCI. The aim of this study was to evaluate associations of dynamic changes of various inflammatory markers with occurrence of DCI after aSAH. METHODS: A total of 279 patients with interventional treatment for aSAH were enrolled, and dichotomized according to the occurrence of DCI. Various inflammatory markers, including systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and their dynamic changes were analyzed at four different time points. Receiver operating characteristic (ROC) curve analysis with area under the curve (AUC) and univariate, multivariate Cox regression analyses with hazard ratio (HR) and 95 % confidence interval (CI) were performed to identify predictors for DCI. RESULTS: Differences of SII and SIRI values between DCI (+) and DCI (-) group were significantly higher at 5-7 days than at other time points (P < 0.001 and P < 0.001, respectively). SII and SIRI had higher predicting values for DCI occurrence than other inflammatory markers (AUC: 0.862, 95 % CI: 0.786-0.928; P < 0.001 and AUC: 0.851, 95 % CI: 0.769-0.913; P < 0.001, respectively). SII at 5-7 days (HR: 1.74, 95 % CI: 1.38-3.22, P = 0.020) and SIRI at 5-7 days (HR: 1.62, 95 % CI: 1.28-2.84, P = 0.035) were associated with occurrence of DCI. CONCLUSIONS: Dynamic changes of SII and SII might be predictors of DCI occurrence in patients with aSAH.

Comparison of Tepotinib, Paclitaxel, or Ramucirumab Efficacy According to the Copy Number or Phosphorylation Status of the MET Gene: Doublet Treatment versus Single Agent Treatment.

Although conventional combination chemotherapies for advanced gastric cancer (GC) increase survival, such therapies are associated with major adverse effects; more effective and less toxic treatments are required. Combinations of different anti-cancer drugs, for example, paclitaxel plus ramucirumab, have recently been used as second-line treatments for advanced GC. This study evaluated how copy number variations of the MET gene, MET mutations, and MET gene and protein expression levels in human GC cells modulate the susceptibility of such cells to single-agent (tepotinib, ramucirumab, or paclitaxel) and doublet (tepotinib-plus-paclitaxel or ramucirumab-plus-paclitaxel treatment regimens. Compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibited the growth of GC cells with MET exon 14 skipping mutations and those lacking MET amplification but containing phosphorylated MET; such inhibition was dose-dependent and associated with cell death. Tepotinib-plus-paclitaxel and ramucirumab-plus-paclitaxel similarly inhibited the growth of GC cells lacking MET amplification or MET phosphorylation, again in a dose-dependent manner, but without induction of cell death. However, tepotinib alone or tepotinib-plus-ramucirumab was more effective against c-MET-positive GC cells (>30 copy number variations) than was ramucirumab or paclitaxel alone or ramucirumab-plus-paclitaxel. These in vitro findings suggest that compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibits the growth of c-MET-positive GC cells, cells lacking MET amplification but containing phosphorylated MET, and cells containing MET mutations. Clinical studies are required to confirm the therapeutic effects of these regimens.

Differential Prognostic Impact of IABP-SHOCK II Scores According to Treatment Strategy in Cardiogenic Shock Complicating Acute Coronary Syndrome: From the RESCUE Registry.

Background: Early risk stratification is necessary for optimal determination of the treatment strategy in cardiogenic shock (CS) complicating acute coronary syndrome (ACS). Therefore, we evaluated the prognostic impact of an intra-aortic balloon pump on the cardiogenic shock (IABP-SHOCK) II score according to the treatment strategies in ACS complicated by CS using the RESCUE (REtrospective and prospective observational Study to investigate Clinical oUtcomes and Efficacy of left ventricular assist device for Korean patients with cardiogenic shock) registry. Methods: The RESCUE registry contains multicenter observational retrospective and prospective cohorts that include 1247 patients with CS from 12 centers in Korea. A total of 865 patients with ACS complicated by CS were selected and stratified into low-, intermediate- and high-risk categories according to their IABP-SHOCK II scores and then according to treatment: non-mechanical support, IABP, and extracorporeal membrane oxygenators (ECMOs). The primary outcome was all-cause mortality during follow-up. Results: The observed mortality rates for the low-, intermediate-, and high-IABP-SHOCK II score risk categories were 28.8%, 52.4%, and 69.8%, respectively (p < 0.01). Patients in the non-mechanical support and IABP groups showed an increasingly elevated risk of all-cause mortality as their risk scores increased from low to high. In the ECMO group, the risk of all-cause mortality did not differ between the intermediate- and high-risk categories (HR = 1.21, 95% CI: 0.81-1.81, p = 0.33). The IABP-SHOCK II scores for the non-mechanical support and IABP groups showed a better predictive performance (area under curve [AUC] = 0.70, 95% CI: 0.65-0.76) for mortality compared with the EMCO group (AUC = 0.61, 95% CI 0.54-0.67; p-value for comparison = 0.02). Conclusions: Risk stratification using the IABP-SHOCK II score is useful for predicting mortality in ACS complicated by CS when patients are treated with non-mechanical support or IABP. However, its prognostic value may be unsatisfactory in severe cases where patients require ECMOs.

Urolithiasis in Kidney Transplant Patients: A Multicenter KSER Research Series.

Background and Objectives: Urolithiasis occurrence is uncommon in kidney transplantation patients, though it has serious implications, including acute kidney injury in the transplanted kidney. This study investigates the leading causes of urolithiasis in kidney transplantation patients, the diagnostic process, and the outcomes of multimodal management. Materials and Methods: Data collection spanned from January 1997 to December 2021, involving kidney transplantation patients with urolithiasis from the database of the Korean Society of Endourology and Robotics (KSER) research committee. Analysis encompassed factors triggering urolithiasis, the diagnostic process, stone attributes, treatment methods, and outcomes. Results: Our analysis included 58 kidney transplantation patients with urolithiasis from eight medical centers. Of these patients, 37 were male and 4 had previous urolithiasis diagnoses. The mean age was 59.09 ± 10.70 years, with a mean duration from kidney transplantation to diagnosis of 76.26 ± 183.14 months. The most frequent method of stone detection was through asymptomatic routine check-ups (54.7%). Among the 58 patients, 51 underwent stone treatment. Notably, 95.3% of patients with ureter stones received treatment, a significantly higher rate than the 66.7% of patients with renal stones (p = 0.010). Success rates showed no significant differences between renal (70%) and ureter stone (78.0%) groups (p = 0.881). Conclusions: Urolithiasis in transplanted kidneys constitutes an acute condition requiring emergency intervention. Endo-urological interventions are effective for kidney transplantation patients with urolithiasis. To ensure prevention and early detection, diligent follow-up and routine imaging tests are necessary.

Mycobacterium potentiates protection from colorectal cancer by gut microbial alterations.

Not only are many Mycobacteria pathogens, but they can act as strong non-specific immunopotentiators, generating beneficial effects on the pathogenesis of some diseases. However, there has been no direct evidence of the effect of mycobacterial species on colorectal cancer (CRC). Herein, we showed that there may be a meaningful inverse correlation between the incidence of tuberculosis and CRC based on global statistics and that heat-killed Mycobacterial tuberculosis and live Mycobacterium bovis (Bacillus Calmette-Guérin strain) could ameliorate CRC development. In particular, using a faecal microbiota transplantation and a comparison between separate housing and cohousing, we demonstrated that the gut microbiota is involved in the protective effects. The microbial alterations can be elucidated by the modulation of antimicrobial activities including those of the Reg3 family genes. Furthermore, interleukin-22 production by T helper cells contributed to the anti-inflammatory activity of Mycobacteria. Our results revealed a novel role of Mycobacteria involving gut microbial alterations in dampening inflammation-associated CRC and an immunological mechanism underlying the interaction between microbes and host immunity.

Microscopic Evidence of Malaria Infection in Visceral Tissue from Medici Family, Italy.

Microscopy of mummified visceral tissue from a Medici family member in Italy identified a potential blood vessel containing erythrocytes. Giemsa staining, atomic force microscopy, and immunohistochemistry confirmed Plasmodium falciparum inside those erythrocytes. Our results indicate an ancient Mediterranean presence of P. falciparum, which remains responsible for most malaria deaths in Africa.

RERE deficiency contributes to the development of orofacial clefts in humans and mice.

Deletions of chromosome 1p36 are the most common telomeric deletions in humans and are associated with an increased risk of orofacial clefting. Deletion/phenotype mapping, combined with data from human and mouse studies, suggests the existence of multiple 1p36 genes associated with orofacial clefting including SKI, PRDM16, PAX7 and GRHL3. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in the proximal critical region for 1p36 deletion syndrome and encodes a nuclear receptor co-regulator. Pathogenic RERE variants have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye or heart (NEDBEH). Cleft lip has previously been described in one individual with NEDBEH. Here we report the first individual with NEDBEH to have a cleft palate. We confirm that RERE is broadly expressed in the palate during mouse embryonic development, and we demonstrate that the majority of RERE-deficient mouse embryos on C57BL/6 background have cleft palate. We go on to show that ablation of Rere in cranial neural crest (CNC) cells, mediated by a Wnt1-Cre, leads to delayed elevation of the palatal shelves and cleft palate and that proliferation of mesenchymal cells in the palatal shelves is significantly reduced in Rereflox/flox; Wnt1-Cre embryos. We conclude that loss of RERE function contributes to the development of orofacial clefts in individuals with proximal 1p36 deletions and NEDBEH and that RERE expression in CNC cells and their derivatives is required for normal palatal development.

AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20).

BACKGROUND: Loss of PTEN function leads to increased PI3Kß signaling. AZD8186, a selective PI3Kß/δ inhibitor, has shown anti-tumor activity in PTEN-deficient preclinical models. Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed in advanced gastric cancer with PTEN loss. METHODS: In the phase Ib dose-escalation, subjects with advanced solid tumors received oral AZD8186 (60 mg or 120 mg; twice daily (BID); 5 days on/2 days off) plus intravenous paclitaxel (70 mg/m2 or 80 mg/m2; days 1, 8, and 15) every 4 weeks. In the phase II part, MRGC patients with PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received recommended phase II dose (RP2D) of AZD8186 plus paclitaxel. Primary endpoints were to determine maximum tolerated dose (MTD) and RP2D in phase Ib and 4-month progression-free survival (PFS) rate in phase II. RESULTS: In phase Ib, both MTD and RP2D were determined at paclitaxel 80 mg/m2 and AZD8186 120 mg BID. In phase II, 18 patients were enrolled [PTEN loss (n = 18) and PIK3CB mutation (n = 1)]. The 4-month PFS rate was 18.8% (3 of 16 evaluable patients) and further enrollment stopped due to futility. CONCLUSION: Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed.ClinicalTrials.gov Identifier: NCT04001569.

Different Impact of Metabolic Syndrome on the Risk of Incidence of the Peripheral Artery Disease and the Venous Thromboembolism: A Nationwide Longitudinal Cohort Study in South Korea.

Background: Limited data is available between metabolic syndrome (MetS) and the development of peripheral arterial disease (PAD) or venous thromboembolism (VTE) in the Asian population. We investigated the incidence of PAD and VTE according to the prevalence of MetS and evaluated the impact of individual components in MetS on the development of PAD and VTE using Korean national data. Methods: Data obtained from national health screening examinations of the Korean National Health Insurance Service from January 1, to December 31, 2009. In total, 9,927,538 participants, 7,830,602 participants were included in this study and the incidence rate of PAD and VTE was investigated retrospectively during a 7-year follow-up. Using the National Cholesterol Education Program Adult Treatment Panel III criteria, patients were placed into one of three groups depending on MetS component numbers: 0 (normal), 1-2 (Pre-MetS), or 3-5 (MetS). Results: The incidence rates of PAD and VTE in MetS were 2.25% and 0.71%, respectively. After multivariable adjustment, the risk of PAD was significantly associated with MetS (hazard ratio (HR) 1.45, 95% confidence interval (CI) 1.42-1.49), the risk of VTE was not associated with MetS (HR 1.01, 95% CI 0.96-1.05). When subgroup analyses were conducted according to MetS components, elevated fasting glucose (HR 1.26, 95% CI 1.23-1.27), abdominal obesity (HR 1.15, 95% CI 1.12-1.17), and elevated blood pressure (HR 1.13, 95% CI 1.12-1.15) were the most related to PAD. Abdominal obesity (HR 1.104, 95% CI 1.064-1.146) was associated with an increased risk of VTE. Conclusions: MetS was significantly associated with an increased incidence rate of PAD among the general Korean population. On the other hand, MetS was not associated with the VTE incidence rate. Of the MetS components, only abdominal obesity was a significant predictor of VTE.