A novel chicken-origin colistin-resistant Klebsiella pneumoniae ST5982 Co-harboring mcr-3.11 and CTX-M-27.

Klebsiella pneumoniae (K. pneumoniae) is an important zoonotic opportunistic pathogen of Enterobacteriaceae that has become one of the most common infectious diseases causing Enterobacteriaceae after Escherichia coli. In this study, we identified a colistin-resistant, multidrug-resistant ST5982 K. pneumoniae strain of broiler origin. The isolate carried 35 resistance genes of 10 antibiotics classes, detected by whole genome sequencing (WGS); 11.4 % (4/35) of the resistance genes were distributed in the chromosome, and 88.6 % (31/35) of the resistance genes were located in four different resistance plasmids. Among the four plasmids, we found for the first time that CTX-M-27 and mcr-3.11 simultaneously coexisted in K. pneumoniae, and a resistance plasmid of IncI1 carrying a combination of mcr-3.11 and qnrS1 was identified. We successfully transferred mcr-3.11, qnrS1 and CTX-M-27 genes into E. coli J53 through conjugation experiments. In the present study, the co-occurrence of CTX-M-27 and mcr-3.11 in multidrug-resistant K. pneumoniae strain ST5982 was detected for the first time; its drug resistance was evaluated, and the risk of its transmission was assessed to provide a reference for further prevention and treatment of K. pneumoniae.

Chemical inhibition of stomatal differentiation by perturbation of the master-regulatory bHLH heterodimer via an ACT-Like domain.

Selective perturbation of protein interactions with chemical compounds enables dissection and control of developmental processes. Differentiation of stomata, cellular valves vital for plant growth and survival, is specified by the basic-helix-loop-helix (bHLH) heterodimers. Harnessing a new amination reaction, we here report a synthesis, derivatization, target identification, and mode of action of an atypical doubly-sulfonylated imidazolone, Stomidazolone, which triggers stomatal stem cell arrest. Our forward chemical genetics followed by biophysical analyses elucidates that Stomidazolone directly binds to the C-terminal ACT-Like (ACTL) domain of MUTE, a master regulator of stomatal differentiation, and perturbs its heterodimerization with a partner bHLH, SCREAM in vitro and in plant cells. On the other hand, Stomidazolone analogs that are biologically inactive do not bind to MUTE or disrupt the SCREAM-MUTE heterodimers. Guided by structural docking modeling, we rationally design MUTE with reduced Stomidazolone binding. These engineered MUTE proteins are fully functional and confer Stomidazolone resistance in vivo. Our study identifies doubly-sulfonylated imidazolone as a direct inhibitor of the stomatal master regulator, further expanding the chemical space for perturbing bHLH-ACTL proteins to manipulate plant development.

Prominin-1 null Xenopus laevis develop subretinal drusenoid-like deposits, cone-rod dystrophy, and RPE atrophy.

PROMININ-1 (PROM1) mutations are associated with inherited, non-syndromic vision loss. We used CRISPR/Cas9 to induce prom1-null mutations in Xenopus laevis and then tracked retinal disease progression from the ages of 6 weeks to 3 years old. Prom1-null associated retinal degeneration in frogs is age-dependent and involves RPE dysfunction preceding photoreceptor degeneration. Before photoreceptor degeneration occurs, aging prom1-null frogs develop increasing size and numbers of cellular debris deposits in the subretinal space and outer segment layer, which resemble subretinal drusenoid deposits (SDD) in their location, histology, and representation in color fundus photography and optical coherence tomography (OCT). Evidence for an RPE origin of these deposits includes infiltration of pigment granules into the deposits, thinning of RPE as measured by OCT, and RPE disorganization as measured by histology and OCT. The appearance and accumulation of SDD-like deposits and RPE thinning and disorganization in our animal model suggests an underlying disease mechanism for prom1-null mediated blindness of death and dysfunction of the RPE preceding photoreceptor degeneration, instead of direct effects upon photoreceptor outer segment morphogenesis, as was previously hypothesized.

Dietary patterns related to attention and physiological function in high-altitude migrants.

High altitude exposure negatively affects human attentional function. However, no studies have explored the regulation of attentional and physiological functions from a dietary perspective. A total of 116 Han Chinese students from Tibet University who were born and raised in a plain area and had been living in Tibet for > 2 years were recruited. All participants were male migrants. A food frequency questionnaire, complete blood count, and attention network test were performed on the participants. Pearson's correlation was applied to assess the reliability and validity of the food frequency questionnaire. Principal component analysis was utilized to extract dietary patterns. A linear mixed model was employed to account for individual differences. The results showed that the five main dietary patterns were coarse grain, alcohol, meat, protein, and snacking dietary patterns. Furthermore, individuals who adhered to the coarse grain dietary pattern and had high mean corpuscular hemoglobin showed better attentional performance. Individuals with high alcohol consumption and systemic immune-inflammation index levels exhibited worse attentional performance. These findings imply that high-altitude migrants should include more coarse grains in their daily diet and avoid excessive alcohol consumption to improve attention.

Airway management for right thoracoscopic tracheal tumour resection after left pneumonectomy assisted by cardiopulmonary bypass: a case report.

BACKGROUND: The incidence of secondary tracheal tumours following lung cancer surgery is notably low. Patients with tracheal tumours typically present with symptoms such as coughing, sputum production, haemoptysis, wheezing, stridor, and dyspnoea. In cases of peripheral structure invasion, symptoms may further extend to hoarseness and dysphagia. Initial symptoms may be notably non-distinct. However, the development of pronounced airway symptoms often signifies a critical condition. CASE PRESENTATION: A 70-year-old male with severe chest tightness and asthma was transferred to our hospital for emergency treatment. He had undergone left pneumonectomy for non-small cell carcinoma of the left upper lobe of the lung 3 years prior. The examination confirmed that a secondary tumour originated from the left main bronchus and extended to the carina, occupying 90% of the diameter of the tracheal lumen. To relieve the patient's emergency airway, we chose right thoracoscopic resection of the tracheal tumour assisted by cardiopulmonary bypass (CPB), which provides extracorporeal lung support and a good surgical field. CONCLUSION: In patients with secondary tracheal tumours after left pneumonectomy for lung cancer, perioperative airway management is challenging for anaesthesiologists, and patients' oxygenation should receive close attention. This article describes the airway management process of this patient for reference.

New ABL1 Kinase Domain Mutations in BCR::ABL1-Positive Acute Lymphoblastic Leukemia.

BACKGROUND: Since the development of the first-generation Tyrosine Kinase Inhibitor (TKI), it has played a crucial role in the treatment of BCR::ABL1-positive acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). However, ABL1 kinase domain (ABL1 KD) mutations confer resistance to several TKIs. These mutations have been extensively studied in chronic myeloid leukemia (CML) but less so in BCR::ABL1-positive acute lymphoblastic leukemia (ALL). METHODS: Our study aimed to analyze the the ABL1 KD mutations in 97 consecutive newly-diagnosed adults with BCR::ABL1-positive ALL before therapy, in cytogenetic complete remission and at relapse with next generation sequencing (NGS). The relationship between ABL1 KD mutations and TKI selection was also analyzed. RESULTS: Previously unreported ABL1 KD mutations R239G, F401V/L, R516L and K262T were the most prevalent in pre-therapy and cytogenetic remission samples, whereas T315I/P and P-loop mutations were most prevalent in relapse samples. R239G, F401V/L, R516L and K262T are related to the BCR::ABL1 structure, whereas T315I/P and P-loop mutations directly alter kinase activity. BaF3 cells transfected with ABL1 KD F401V, K262T, R239G, or R516L mutations were resistant to imatinib but strongly inhibited by olverembatinib with IC50 values of 0.73 to 1.52nM. Meanwhile, olverembatinib had advantages in increasing complete molecular response (CMR) and good prognosis. CONCLUSION: Overall, our findings indicate the prevalence and impact of new ABL1 KD mutations in BCR::ABL1-positive ALL patients, highlighting the necessity for effective therapies targetingthese mutations.

Assessment of palpitations in patients with frequent premature ventricular contractions.

INTRODUCTION: In patients with frequent premature ventricular contractions (PVCs), palpitations may not always be directly caused by PVCs, and therefore, it is essential to establish symptom-rhythm correlations to determine the appropriate treatment. This study aims to analyze the palpitations and related factors in patients with frequent PVCs. METHODS: The study enrolled patients with frequent PVCs who were not combined with other arrhythmias or structural heart disease. Through face-to-face consultation, patients were divided into symptomatic and asymptomatic groups. For symptomatic patients, the correlation between palpitations and PVC was further evaluated based on the temporal consistency of symptom onset and PVC occurrence. The demographic, clinical, and electrocardiogram features of the patients in each group were compared. RESULTS: Of the 214 patients enrolled, 124(57.9%) experienced palpitations. Compared to the asymptomatic group, the symptomatic group had a higher proportion of females (63.7% vs. 47.8%; p = .020) and a higher proportion of subjects with anxiety (44.4% vs.14.4%; p = .000). Within the symptomatic patients, 72 (33.60%) who had palpitations that were clearly correlated with PVCs were classified as the PVC-relevant group. In this group, the PVC CI ratios were significantly lower (55% [52% -60%] vs. 62% [55% -67%]; p = .001) and the Post-PVC CI were longer (1170 [1027-1270] vs. 1083 [960-1180] ms; p = .018) than in the PVC-irrelevant group. CONCLUSION: A direct relationship between palpitations and PVCs could be established only in a minority of patients with frequent PVCs. PVCs with a relatively short PVC CI and a long post-PVC CI were more likely to cause palpitations, whereas palpitations lasting only a few seconds were more likely to be directly relevant to PVCs.

Functional characterization of CaSOC1 at low temperatures and its role in low-temperature escape.

Environmental factors such as light and temperature tightly regulate plant flowering time. Under stressful conditions, plants inhibit vegetative growth and accelerate flowering as an emergency response. This adaptive mechanism benefits the survival of species and enhances their reproductive success. This phenomenon is often referred to as stress escape. However, the signaling pathways between low-temperature signals and flowering time are poorly understood. In this study, the MIKC transcription factor, CaSOC1, was isolated from pepper (Capsicum annuum), which showed suppressed expression under low-temperature conditions. Silencing the expression of CaSOC1 in pepper plants resulted in reduced photosynthetic capacity, inhibited vegetative growth, and increased sensitivity to low temperatures. In contrast, overexpression of CaSOC1 increased the biomass of tomato plants under normal growth conditions but suppressed their antioxidant enzyme activity at low temperatures, which negatively regulated their cold tolerance. Furthermore, intermittent low-temperature treatment with CaSOC1 overexpression promoted early flowering in tomato plants. Our findings demonstrate that CaSOC1 reduced the cold tolerance of pepper plants under short term low-temperature conditions, whereas intermittent low-temperature treatment enhanced flower bud differentiation, enabling stress escape and adaptation to long low-temperature environments.

Assessment of acute radial artery injury after distal transradial access for coronary intervention: an optical coherence tomography study.

There is a paucity of data on acute radial artery (RA) injuries using optical coherence tomography (OCT) in patients undergoing coronary intervention via distal transradial coronary access (dTRA). To evaluate the incidence of acute RA injury following dTRA for coronary intervention using OCT. We retrospectively analyzed 200 consecutive patients with acute coronary syndrome (ACS) who underwent coronary intervention guided by OCT and RA-OCT after dTRA at our center between June 2021 and November 2022. Total length of RA was divided into three segments based on the sheath location during dTRA: no sheath protection portion (proximal RA segment) and sheath protection portion (divided into mid- and distal segments). Acute RA injuries, including tears, dissections, perforations, thrombi, and spasms, were analyzed. Radial artery occlusion (RAO) was assessed using ultrasonography 24 h after dTRA. Acute RA injury was observed in 45.5% of patients after dTRA. The incidence of tear, dissection, perforation, thrombi, and spasm in all the patients was 11.5%, 16.5%, 1.5%, 17.5%, and 17.5%, respectively. In segment-level analysis, dissection and spasm were significantly more frequent in the proximal segment, followed by the mid and distal segments (11.0% vs. 5.5% vs. 4.5%, P = 0.015; 13.0% vs. 4.0% vs. 4.5%, P = 0.002). The rate of RAO at 24-h follow-up was 3.0%. Acute RA injuries were observed in nearly half of the patients using OCT via dTRA; dissection and spasm occurred more frequently in the proximal segment. Hydrophilic-coated sheaths have the potential advantage of preventing radial artery spasm and dissection.

Effects of Exergaming on executive function and motor ability in children: A systematic review and meta-analysis.

This study aimed to evaluate the effectiveness of Exergaming in improving executive function and motor ability across different groups of children and adolescents. We searched several databases, including PsycINFO, Web of Science, Embase, PubMed, SPORT Discus, Scopus, and the Cochrane Central Register of Controlled Trials, for randomized controlled trial (RCT) studies published from inception until November 25, 2023, to identify studies investigating the effect of Exergaming on motor and executive function in children. The protocol was registered with PROSPERO (CRD42023482281). A total of 37 randomized controlled trials were included in this study. Our results indicate that Exergaming can influence children's cognitive flexibility [SMD = 0.34, 95%CI(0.13,0.55), I2 = 0.0%, P = 0.738], inhibition control [SMD = 0.51, 95%CI (0.30,0.72), I2 = 0.0%, P = 0.473], global cognitive [SMD = 0.87, 95%CI (0.50,1.23), I2 = 0.0%, P = 0.974], working memory [SMD = 0.18, 95%CI(-0.16, 0.52), I2 = 46.5%, P = 0.096], gross motor skills [SMD = 0.82, 95%CI (0.30, 1.35), I2 = 79.1%, P<0.001], fine motor skills [SMD = 0.71, 95%CI (0.22,1.21), I2 = 78.7%, P<0.001], balance [SMD = 0.61, 95%CI (0.34, 0.88), I2 = 59.5%, P = 0.001], and cardiorespiratory [SMD = 0.48, 95%CI (0.16, 0.79), I2 = 58.4%, P = 0.019]. While these findings suggest that Exergaming can promote children's cognitive flexibility, inhibitory control, global cognition and motor abilities, the effect on working memory was not statistically significant. Further high-quality randomized controlled trials are warranted to explore the potential benefits of Exergaming for different groups of children, including those with specific needs.

The Role of Alexithymia and Moral Disengagement in Childhood Physical Abuse and Depressive Symptoms: A Comparative Study Among Rural and Urban Chinese College Students.

Purpose: There is robust evidence indicating the adverse association between childhood abuse and depressive symptoms. However, the ways in which childhood physical abuse is indirectly associated with adulthood depressive symptoms by alexithymia and moral disengagement remain poorly understood, particularly in the context of China. The present study aims to investigate how childhood physical abuse may be associated with depressive symptoms via the serial mediation effects of alexithymia and moral disengagement among college students in China. Methods: A total of 686 college students (female: 53.2%) aged from 17 to 28 years old (M = 21.33; SD = 2.53) were recruited from mainland China to participate in an online survey assessing the variables of interest. Structural equation modeling and multiple group analysis were performed using Mplus 7.0 to investigate the hypothesized model. Results: College students' experiences with childhood physical abuse was significantly associated with their depressive symptoms. This relationship was partially mediated by alexithymia and then by moral disengagement. Meanwhile, alexithymia and moral disengagement had a chain mediating effect on childhood physical abuse and depressive symptoms. Furthermore, multigroup analysis revealed that the association between alexithymia and depressive symptoms was stronger among rural students compared to urban students. Furthermore, the mediation model involving moral disengagement applies exclusively to rural students. Conclusion: Alexithymia and moral disengagement exerted serial mediating effect on the association between childhood physical abuse and depressive symptoms. This pattern was particularly pronounced among rural students. These findings underscore the importance of addressing both childhood adversity and maladaptive cognitive processes in the prevention and treatment of depression.

Phospholipid peroxidation in macrophage confers tumor resistance by suppressing phagocytic capability towards ferroptotic cells.

Ferroptosis holds significant potential for application in cancer therapy. However, ferroptosis inducers are not cell-specific and can cause phospholipid peroxidation in both tumor and non-tumor cells. This limitation greatly restricts the use of ferroptosis therapy as a safe and effective anticancer strategy. Our previous study demonstrated that macrophages can engulf ferroptotic cells through Toll-like receptor 2 (TLR2). Despite this advancement, the precise mechanism by which phospholipid peroxidation in macrophages affects their phagocytotic capability during treatment of tumors with ferroptotic agents is still unknown. Here, we utilized flow sorting combined with redox phospholipidomics to determine that phospholipid peroxidation in tumor microenvironment (TME) macrophages impaired the macrophages ability to eliminate ferroptotic tumor cells by phagocytosis, ultimately fostering tumor resistance to ferroptosis therapy. Mechanistically, the accumulation of phospholipid peroxidation in the macrophage endoplasmic reticulum (ER) repressed TLR2 trafficking to the plasma membrane and caused its retention in the ER by disrupting the interaction between TLR2 and its chaperone CNPY3. Subsequently, this ER-retained TLR2 recruited E3 ligase MARCH6 and initiated the proteasome-dependent degradation. Using redox phospholipidomics, we identified 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH) as the crucial mediator of these effects. Conclusively, our discovery elucidates a novel molecular mechanism underlying macrophage phospholipid peroxidation-induced tumor resistance to ferroptosis therapy and highlights the TLR2-MARCH6 axis as a potential therapeutic target for cancer therapy.

An integrated micromachined flexible ultrasonic-inductive sensor for pipe contaminant multiparameter detection.

Pipe contaminant detection holds considerable importance within various industries, such as the aviation, maritime, medicine, and other pertinent fields. This capability is beneficial for forecasting equipment potential failures, ascertaining operational situations, timely maintenance, and lifespan prediction. However, the majority of existing methods operate offline, and the detectable parameters online are relatively singular. This constraint hampers real-time on-site detection and comprehensive assessments of equipment status. To address these challenges, this paper proposes a sensing method that integrates an ultrasonic unit and an electromagnetic inductive unit for the real-time detection of diverse contaminants and flow rates within a pipeline. The ultrasonic unit comprises a flexible transducer patch fabricated through micromachining technology, which can not only make installation easier but also focus the sound field. Moreover, the sensing unit incorporates three symmetrical solenoid coils. Through a comprehensive analysis of ultrasonic and induction signals, the proposed method can be used to effectively discriminate magnetic metal particles (e.g., iron), nonmagnetic metal particles (e.g., copper), nonmetallic particles (e.g., ceramics), and bubbles. This inclusive categorization encompasses nearly all types of contaminants that may be present in a pipeline. Furthermore, the fluid velocity can be determined through the ultrasonic Doppler frequency shift. The efficacy of the proposed detection principle has been validated by mathematical models and finite element simulations. Various contaminants with diverse velocities were systematically tested within a 14 mm diameter pipe. The experimental results demonstrate that the proposed sensor can effectively detect contaminants within the 0.5-3 mm range, accurately distinguish contaminant types, and measure flow velocity.

Short-Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation.

Statins, the first-line medication for dyslipidemia, are linked to an increased risk of type 2 diabetes. But exactly how statins cause diabetes is yet unknown. In this study, a developed short-term statin therapy on hyperlipidemia mice show that hepatic insulin resistance is a cause of statin-induced diabetes. Statin medication raises the expression of progesterone and adiponectin receptor 9 (PAQR9) in liver, which inhibits insulin signaling through degradation of protein phosphatase, Mg2+/Mn2+ dependent 1 (PPM1α) to activate ERK pathway. STIP1 homology and U-box containing protein 1 (STUB1) is found to mediate ubiquitination of PPM1α promoted by PAQR9. On the other hand, decreased activity of hepatocyte nuclear factor 4 alpha (HNF4α) seems to be the cause of PAQR9 expression under statin therapy. The interventions on PAQR9, including deletion of PAQR9, caloric restriction and HNF4α activation, are all effective treatments for statin-induced diabetes, while liver specific over-expression of PPM1α is another possible tactic. The results reveal the importance of HNF4α-PAQR9-STUB1-PPM1α axis in controlling the statin-induced hepatic insulin resistance, offering a fresh insight into the molecular mechanisms underlying statin therapy.

Effect of supraglottic jet oxygenation and ventilation on hypoxemia in patients undergoing endoscopic surgery with sedation: A meta-analysis of randomized controlled trials.

BACKGROUND: Nasal cannulas and face masks are common oxygenation tools used in conventional oxygen therapy for patients undergoing endoscopic surgery with sedation. However, as a novel supraglottic ventilation technique, the application of supraglottic jet oxygenation and ventilation (SJOV) in endoscopic surgery has not been well established. METHOD: We searched six electronic databases from inception to January 16, 2024, to assess the oxygenation/ventilation efficacy and side effects of the of SJOV in endoscopic surgery. The primary outcome was the incidence of hypoxemia. The secondary outcomes were the incidence of respiratory depression and adverse effects (nasal bleeding, sore throat, and dry mouth). RESULTS: Nine trials involving 2017 patients were included. The results demonstrated that the incidence of hypoxemia was lower in the SJOV group compared with the conventional oxygen therapy (COT) group [9 trails; 2017 patients; risk ratio (RR) = 0.18; 95% confidence interval (CI), (0.11-0.28)]. Subgroup analyses showed that SJOV reduced the incidence of hypoxemia in the high-risk group but had no effect on the low-risk group. The incidence of respiratory depression is lower in SJOV than in COT, but has increased side effects such as dry mouth. There was no statistically significant difference in nose bleeding or sore throat between the two groups. CONCLUSION: Compared with the COT, the SJOV decreased the incidence of hypoxemia in high-risk patients during endoscopic surgery with sedation. There was an increased risk of dry mouth, but not of nose bleeding or sore throat, during endoscopic surgery under sedation.

Global expansion of tropical cyclone precipitation footprint.

Precipitation from tropical cyclones (TCs) can cause massive damage from inland floods and is becoming more intense under a warming climate. However, knowledge gaps still exist in changes of spatial patterns in heavy TC precipitation. Here we define a metric, DIST30, as the mean radial distance from centers of clustered heavy rainfall cells (> 30 mm/3 h) to TC center, representing the footprint of heavy TC precipitation. There is significant global increase in DIST30 at a rate of 0.34 km/year. Increases of DIST30 cover 59.87% of total TC impact areas, with growth especially strong in the Western North Pacific, Northern Atlantic, and Southern Pacific. The XGBoost machine learning model showed that monthly DIST30 variability is majorly controlled by TC maximum wind speed, location, sea surface temperature, vertical wind shear, and total water column vapor. TC poleward migration in the Northern Hemisphere contributes substantially to the DIST30 upward trend globally.

Characterizing Retinal Sensitivity and Structure in Congenital Stationary Night Blindness: A Combined Microperimetry and OCT Study.

Purpose: To investigate the characteristics of microperimetry and optical coherence tomography (OCT) in congenital stationary night blindness (CSNB), as well as their structure-function association. Methods: This cross-sectional study included 32 eyes from 32 participants with CSNB, comprising 18 with complete CSNB and 14 with incomplete CSNB, along with 36 eyes from 36 CSNB-unaffected controls matched for age, sex, and spherical equivalent. Using MP-3 microperimetry, central retinal sensitivity was assessed within a 20° field, distributed across six concentric rings (0°, 2°, 4°, 6°, 8°, and 10°). OCT was used to analyze retinal and choroidal thickness. The study aimed to assess the overall and ring-wise retinal sensitivity, as well as choroidal and retinal thickness in CSNB and CSNB-unaffected controls, with a secondary focus on the relationship between retinal sensitivity and microstructural features on OCT. Results: In comparison with CSNB-unaffected subjects, the overall and ring-wise retinal sensitivity as well as choroidal thickness were reduced in patients with CSNB (P < 0.001). Moreover, the central sensitivity in incomplete CSNB group was lower than in complete CSNB group (25.72 ± 3.93 dB vs. 21.92 ± 4.10 dB; P < 0.001). The retinal thickness in the CSNB group was thinner outside the fovea compared with the CSNB-unaffected group. Multiple mixed regression analyses revealed that point-to-point retinal sensitivity was significantly correlated with BCVA (P = 0.002) and the corresponding retinal thickness (P = 0.004). Conclusions: Examination of retinal sensitivity and OCT revealed different spatial distribution profiles in CSNB and its subtypes. In CSNB eyes, retinal sensitivity on microperimetry was associated with retinal thickness on OCT.

Population-Level Identification of Patients With Lynch Syndrome for Clinical Care, Quality Improvement, and Research.

PURPOSE: Identification of those at risk of hereditary cancer syndromes using electronic health record (EHR) data sources is important for clinical care, quality improvement, and research. We describe diagnostic processes, previously seldom reported, for a common hereditary cancer syndrome, Lynch syndrome (LS), using EHR data within a community-based, multicenter, demographically diverse health system. METHODS: Within a retrospective cohort enrolled between 2015 and 2020 at Kaiser Permanente Northern California, we assessed electronic diagnostic domains for LS including (1) family history of LS-associated cancer; (2) personal history of LS-associated cancer; (3) LS screening via mismatch repair deficiency (MMRD) testing of newly diagnosed malignancy; (4) germline genetic test results; and (5) clinician-entered diagnostic codes for LS. We calculated proportions and overlap for each diagnostic domain descriptively. RESULTS: Among 5.8 million individuals, (1) 28,492 (0.49%) had a family history of LS-associated cancer of whom 3,635 (13%) underwent genetic testing; (2) 100,046 (1.7%) had a personal history of a LS-associated cancer; and (3) 8,711 (0.1%) were diagnosed with colorectal cancer of whom 7,533 (86%) underwent MMRD screening and of the positive screens (486), 130 (27%) underwent germline testing. One thousand seven hundred and fifty-seven (0.03%) were diagnosed with endometrial cancer of whom 1,613 (92%) underwent MMRD screening and of the 195 who screened positive, 55 (28%) underwent genetic testing. (4) 30,790 (0.05%) had LS germline genetic testing with 707 (0.01%) testing positive; and (5) 1,273 (0.02%) had a clinician-entered diagnosis of LS. CONCLUSION: It is feasible to electronically characterize the diagnostic processes of LS. No single data source comprehensively identifies all LS carriers. There is underutilization of LS genetic testing for those eligible and underdiagnosis of LS. Our work informs similar efforts in other settings for hereditary cancer syndromes.

Prominin-1 null Xenopus laevis develop subretinal drusenoid-like deposits, cone-rod dystrophy, and RPE atrophy.

Mutations in the PROMININ-1 (PROM1) gene are associated with inherited, non-syndromic vision loss. Here, we used CRISPR/Cas9 to induce truncating prom1-null mutations in Xenopus laevis to create a disease model. We then tracked progression of retinal degeneration in these animals from the ages of 6 weeks to 3 years old. We found that retinal degeneration caused by prom1-null is age-dependent and likely involves death or damage to the retinal pigment epithelium (RPE) that precedes photoreceptor degeneration. As prom1-null frogs age, they develop large cellular debris deposits in the subretinal space and outer segment layer which resemble subretinal drusenoid deposits (SDD) in their location, histology, and representation in color fundus photography and optical coherence tomography (OCT). In older frogs, these SDD-like deposits accumulate in size and number, and they are present before retinal degeneration occurs. Evidence for an RPE origin of these deposits includes infiltration of pigment granules into the deposits, thinning of RPE as measured by OCT, and RPE disorganization as measured by histology and OCT. The appearance and accumulation of SDD-like deposits and RPE thinning and disorganization in our animal model suggests an underlying disease mechanism for prom1-null mediated blindness of death and dysfunction of the RPE preceding photoreceptor degeneration, instead of direct effects upon photoreceptor outer segment morphogenesis, as was previously hypothesized.

BATF-dependent Th17 cells act through the IL-23R pathway to promote prostate adenocarcinoma initiation and progression.

BACKGROUND: The role of Th17 cells in prostate cancer is not fully understood. The transcription factor BATF controls the differentiation of Th17 cells. Mice deficient in Batf do not produce Th17 cells. METHODS: In this study, we aimed to characterize the role of Batf-dependent Th17 cells in prostate cancer by crossbreeding Batf knockout mice with mice conditionally mutant for Pten. RESULTS: We found that Batf knockout mice had changes in the morphology of prostate epithelial cells compared with normal mice, and Batf knockout mice deficient in Pten (called Batf-) had smaller prostate size and developed fewer invasive prostate adenocarcinomas than Pten-deficient mice with Batf expression (called Batf+). The prostate tumors in Batf- mice showed reduced proliferation, increased apoptosis, decreased angiogenesis and inflammatory cell infiltration, and activation of nuclear factor-κB signaling. Moreover, Batf- mice showed significantly reduced interleukin 23 (IL-23)-IL-23R signaling. In the prostate stroma of Batf- mice, IL-23R-positive cells were decreased considerably compared with Batf+ mice. Splenocytes and prostate tissues from Batf- mice cultured under Th17 differentiation conditions expressed reduced IL-23/IL-23R than cultured cells from Batf+ mice. Anti-IL-23p19 antibody treatment of Pten-deficient mice reduced prostate tumors and angiogenesis compared with control immunoglobulin G-treated mice. In human prostate tumors, BATF messenger RNA level was positively correlated with IL-23A and IL-23R but not RORC. CONCLUSION: Our novel findings underscore the crucial role of IL-23-IL-23R signaling in mediating the function of Batf-dependent Th17 cells, thereby promoting prostate cancer initiation and progression. This finding highlights the BATF-IL-23R axis as a promising target for the development of innovative strategies for prostate cancer prevention and treatment.