Icotinib in a lung adenocarcinoma patient with acquired EGFR 19del/C797S mutation-mediated resistance to osimertinib: a case report.

Based on the FLAURA and AURA III trials, compared to first- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), osimertinib provides a longer overall survival benefit for patients with untreated EGFR mutated non-small cell lung cancer. Similar to other EGFR-TKIs, drug resistance is, however, inevitable. The most common mechanism of acquired resistance to first-line osimertinib therapy is the C797S mutation, which accounts for 6% of cases. In view of the current challenges of the development of the next generation of EGFR inhibitors, the mechanism of third-generation targeted drug resistances and targeted strategies are key for further exploration. Our case report discusses a female patient with advanced lung adenocarcinoma carrying the EGFR exon19 E746_A750delinsIP mutation who received osimertinib as first-line therapy and acquired C797S resistance during treatment. The patient was then treated with icotinib for 8 months until the disease progressed. Icotinib may be effective in patients with the EGFR 19del-C797S resistant mutation acquired after osimertinib treatment.

Clinical outcomes and aortic remodeling after Castor single-branched stent-graft implantation for type B aortic dissections involving left subclavian artery.

Background: The left subclavian artery (LSA) can be intentionally covered by a stent graft to acquire adequate landing zones for a proximal entry tear near the LSA during thoracic endovascular aortic repair (TEVAR). The Castor single-branched stent graft is designed to treat type B aortic dissection (TBAD) to retain the LSA during TEVAR. This study investigates clinical outcomes, aortic remodeling, and abdominal aortic perfusion patterns after TEVAR with the novel Castor device. Methods: From November 2020 to June 2023, 29 patients with TBAD involving the LSA were treated with the Castor single-branched stent graft. In-hospital clinical outcome and aortic computed tomography angiography (CTA) data were analyzed. CTA was performed preoperatively and at follow-up to observe stent morphology; branch patency; endoleak; change in true lumen (TL), false lumen (FL), and transaortic diameters; and abdominal aortic branch perfusion pattern. Results: The technical success rate was 96.6%. One failure was that the branch section did not completely enter the LSA and the main body migrated distally. No in-hospital mortality, paraplegia, or stroke occurred. During follow-up, one type Ib endoleak, four distal new entry tears, and one recurrent type A dissection arose from a new entry tear at the ascending aorta, no stent migration was observed, and the branch patency rate was 100%. At the thoracic aorta, TL diameters significantly increased, FL diameters markedly decreased, and FL was partially or completely thrombosed in most patients at follow-up. At the abdominal aorta, we observed 33.3% of TL growth and 66.7% of TL stabilization or shrinkage. The initial TL ratio at iliac bifurcation negatively predicted abdominal TL growth after TEVAR with a cutoff of 21.0%. Of the 102 abdominal aortic branches, 94.1% of the branches showed no change in perfusion pattern, 3.9% of the branches had an increased TL perfusion, and 2.0% of the branches had an increased FL contribution. Conclusion: The Castor unibody single-branched stent graft offers an efficient endovascular treatment for TBAD involving the LSA. TEVAR with the Castor device effectively induced thoracic FL thrombosis and thoracic TL enlargement and resulted in abdominal TL growth when the initial TL ratio at iliac bifurcation is less than 21.0%. Abdominal aortic branch perfusion patterns remain relatively stable after TEVAR with the Castor stent graft.

CEACAM6 expression and function in tumor biology: a comprehensive review.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an immunoglobulin superfamily protein primarily expressed on epithelial surfaces and myeloid cells. It plays a significant role in cancer progression by inhibiting apoptosis, promoting drug resistance, and facilitating cancer cell invasion and metastasis. Overexpression of CEACAM6 has been observed in various cancers, including lung, breast, colorectal, and hepatocellular cancers, and is associated with poorer overall survival and disease-free survival. Its differential expression on tumor cell surfaces makes it a promising cancer marker. This review aims to provide a comprehensive summary of CEACAM6's role in different cancer types, its involvement in signaling pathways, and recent advancements in CEACAM6-targeted treatments.

Nerolidol rescues hippocampal injury of diabetic rats through inhibiting NLRP3 inflammasome and regulation of MAPK/AKT pathway.

Despite the observation of diabetes-induced brain tissue damage and impaired learning and memory, the underlying mechanism of damage remains elusive, and effective, targeted therapeutics are lacking. Notably, the NLRP3 inflammasome is highly expressed in the hippocampus of diabetic individuals. Nerolidol, a naturally occurring compound with anti-inflammatory and antioxidant properties, has been identified as a potential therapeutic option for metabolic disorders. However, the ameliorative capacity of nerolidol on diabetic hippocampal injury and its underlying mechanism remain unclear. Network pharmacology and molecular docking was used to predict the signaling pathways and therapeutic targets of nerolidol for the treatment of diabetes. Then established a diabetic rat model using streptozotocin (STZ) combined with a high-fat diet and nerolidol was administered. Morris water maze to assess spatial learning memory capacity. Hematoxylin and eosin and Nissl staining was used to detect neuronal damage in the diabetic hippocampus. Transmission electron microscopy was used to detect the extent of damage to mitochondria, endoplasmic reticulum (ER) and synapses. Immunofluorescence was used to detect GFAP, IBA1, and NLRP3 expression in the hippocampus. Western blot was used to detect apoptosis (Bcl-2, BAX, and Cleaved-Caspase-3); synapses (postsynaptic densifying protein 95, SYN1, and Synaptophysin); mitochondria (DRP1, OPA1, MFN1, and MFN2); ER (GRP78, ATF6, CHOP, and caspase-12); NLRP3 inflammasome (NLRP3, ASC, and caspase-1); inflammatory cytokines (IL-18, IL-1ß, and TNF-α); AKT (P-AKT); and mitogen-activated protein kinase (MAPK) pathway (P-ERK, P-p38, and P-JNK) related protein expression. Network pharmacology showed that nerolidol's possible mechanisms for treating diabetes are the MAPK/AKT pathway and anti-inflammatory effects. Animal experiments demonstrated that nerolidol could improve blood glucose, blood lipids, and hippocampal neuronal damage in diabetic rats. Furthermore, nerolidol could improve synaptic, mitochondrial, and ER damage in the hippocampal ultrastructure of diabetic rats by potentially affecting synaptic, mitochondrial, and ER-related proteins. Further studies revealed that nerolidol decreased neuroinflammation, NLRP3 and inflammatory factor expression in hippocampal tissue while also decreasing MAPK pathway expression and enhancing AKT pathway expression. However, nerolidol improves hippocampal damage in diabetic rats cannot be shown to improve cognitive function. In conclusion, our study reveals for the first time that nerolidol can ameliorate hippocampal damage, neuroinflammation, synaptic, ER, and mitochondrial damage in diabetic rats. Furthermore, we suggest that nerolidol may inhibit NLRP3 inflammasome and affected the expression of MAPK and AKT. These findings provide a new experimental basis for the use of nerolidol to ameliorate diabetes-induced brain tissue damage and the associated disease.

A new species and a replacement name in Cynanchum (Apocynaceae, Asclepiadeae) from China.

Cynanchumpingtaoi S.Jin Zeng, G.D.Tang & Miao Liao, sp. nov. (Apocynaceae) from Yunnan Province, China, is described and illustrated based on morphological and molecular evidence. Its deeply cordate to reniform leaves and campanulate, large flowers show that it is a member of former Raphistemma Wall., which has been included in Cynanchum L.. It is different from all former Raphistemma species by the broadly ovate corolla lobes, purple-red corolla and connivent corona tip slightly exceeding the corolla throat. Meanwhile, Cynanchumlonghushanense G.D.Tang & Miao Liao, nom. nov. is proposed as replacement name for Raphistemmabrevipedunculatum Y.Wan, which was considered a synonym of Cynanchumhooperianum (Blume) Liede & Khanum but is here reinstated as a distinct species because of significant morphological differences.

Comparison of metabolic rates of ropivacaine in cerebrospinal fluid as inferred from plasma concentrations between elderly patients and young patients.

BACKGROUND: With the aging of human society, more and more elderly patients have to undergo surgery and anesthesia. Clinical observations have indicated from time to time that spinal anesthesia in the elderly appears to last longer than in young people, although there is limited research in this area and the mechanism is unclear at present time. This research work is expected to help understand the decline of local anesthetic metabolism in cerebrospinal fluid of elderly patients so as to help them with precise anesthesia and rapid rehabilitation. METHODS: Twenty patients with spinal anesthesia in orthopedic lower limb surgery were selected to study the rate of drug metabolism in cerebrospinal fluid in two age groups, i.e.,18-30 years old and 75-90 years old. Ropivacaine in peripheral blood is used as a probe to reflect the speed of drug metabolism in cerebrospinal fluid. The contents of total Aß protein and hyaluronic acid in the cerebrospinal fluid were investigated as well. RESULTS: The equivalent dose of ropivacaine anesthetizes the elderly group for a longer time. The metabolism rate of ropivacaine in an elderly patient was slower than that of a young patient. No significant difference in total Aß protein between the two groups was observed while hyaluronic acid in the elderly group was significantly higher than that in the young group. CONCLUSIONS: This study shows that the dose of ropivacaine should be reduced when used for anesthesia in elderly patients. The cumulation of ropivacaine and HA appears to imitate the degeneration of central lymphatic circulation metabolism in elderly people.

Disulfide-constrained peptide scaffolds enable a robust peptide-therapeutic discovery platform.

Peptides present an alternative modality to immunoglobulin domains or small molecules for developing therapeutics to either agonize or antagonize cellular pathways associated with diseases. However, peptides often suffer from poor chemical and physical stability, limiting their therapeutic potential. Disulfide-constrained peptides (DCP) are naturally occurring and possess numerous desirable properties, such as high stability, that qualify them as drug-like scaffolds for peptide therapeutics. DCPs contain loop regions protruding from the core of the molecule that are amenable to peptide engineering via direct evolution by use of phage display technology. In this study, we have established a robust platform for the discovery of peptide therapeutics using various DCPs as scaffolds. We created diverse libraries comprising seven different DCP scaffolds, resulting in an overall diversity of 2 x 1011. The effectiveness of this platform for functional hit discovery has been extensively evaluated, demonstrating a hit rate comparable to that of synthetic antibody libraries. By utilizing chemically synthesized and in vitro folded peptides derived from selections of phage displayed DCP libraries, we have successfully generated functional inhibitors targeting the HtrA1 protease. Through affinity maturation strategies, we have transformed initially weak binders against Notch2 with micromolar Kd values to high-affinity ligands in the nanomolar range. This process highlights a viable hit-to-lead progression. Overall, our platform holds significant potential to greatly enhance the discovery of peptide therapeutics.

Extensive Stage Small-Cell Lung Cancer with Cystic Brain Metastases: A Report of Two Cases.

Objective: Cystic brain metastases (BMs) are rare in small cell lung cancer (SCLC), and there are limited data on the treatment and prognosis of cystic BMs. Whole brain radiotherapy has been the mainstay for BMs since several years. Immune checkpoint inhibitors in extensive stage small cell lung cancer (ES-SCLC) have been shown to be suitable for patients who experienced better overall survival and progress-free survival and have been approved as the first-line treatment for ES-SCLC. In this report, we described two ES-SCLC patients developed cystic BMs after immunotherapy, after which the patients continued to treat the primary lesion with immune checkpoint inhibitors and the cystic BMs with radiotherapy. Case Description: Two male patients were diagnosed with ES-SCLC at the first admission and were subsequently treated with immunotherapy plus platinum therapy, during which cystic BMs developed. One patient received whole brain radiotherapy and the other received whole brain radiotherapy and Gamma knife radiosurgery (GKRS). Immunotherapy was continued after the brain lesions were controlled. It has been 33 months since the first patient was diagnosed and is now in stable condition. The other patient achieved an overall survival of 30 months. Conclusion: This report describes two patients with cystic brain metastases in ES-SCLC. Whole brain radiotherapy has a good effect on local control of cystic brain metastases in small cell lung cancer and can significantly improve the symptoms of patients. At the same time, we treat immunotherapy as the first-line treatment, and then perform cross-immunotherapy after disease progression, combined with anti-vascular targeting drugs. The patient did not develop severe iRAEs.

Role of MARK2 in the nervous system and cancer.

Microtubule-Affinity Regulating Kinase 2 (MARK2), a member of the serine/threonine protein kinase family, phosphorylates microtubule-associated proteins, playing a crucial role in cancer and neurodegenerative diseases. This kinase regulates multiple signaling pathways, including the WNT, PI3K/AKT/mTOR (PAM), and NF-κB pathways, potentially linking it to cancer and the nervous system. As a crucial regulator of the PI3K/AKT/mTOR pathway, the loss of MARK2 inhibits the growth and metastasis of cancer cells. MARK2 is involved in the excessive phosphorylation of tau, thus influencing neurodegeneration. Therefore, MARK2 emerges as a promising drug target for the treatment of cancer and neurodegenerative diseases. Despite its significance, the development of inhibitors for MARK2 remains limited. In this review, we aim to present detailed information on the structural features of MARK2 and its role in various signaling pathways associated with cancer and neurodegenerative diseases. Additionally, we further characterize the therapeutic potential of MARK2 in neurodegenerative diseases and cancer, and hope to facilitate basic research on MARK2 and the development of inhibitors targeting MARK2.

Mining significant local spatial association rules for multi-category point data.

Spatial association rule mining can reveal the inherent laws of spatial object interdependence and is an important part of spatial data mining. Most of the existing algorithms for mining local spatial association rules are oriented towards the spatial association between two categories of points and cannot fully reflect the spatial heterogeneity of complex spatial relations among multiple categories of points. In addition, the interactions between points in different categories are often asymmetrical. However, the existing algorithms ignore this asymmetry. To address the above problems, an algorithm for mining local spatial association rules for point data of multiple categories based on position quotients is proposed. First, the proximity relationship between points is determined by an adaptive filter, and the spatial weight value is given according to Gaussian kernel function. Then, the multivariate local colocation quotient of each point is calculated to measure the strength of the local regional spatial association rule. Finally, the Monte Carlo simulation function is used to generate a random sample distribution to test the significance of the results. The algorithm is verified on artificial simulation data and real Point of Interest (POI) data. The experimental results show that the algorithm can identify significant association regions of different spatial association rules for point sets.

Network pharmacology to unveil the mechanism of suanzaoren decoction in the treatment of alzheimer's with diabetes.

BACKGROUND: Suanzaoren Decoction (SZRD), a well-known formula from traditional Chinese medicine, has been shown to have reasonable cognitive effects while relaxing and alleviating insomnia. Several studies have demonstrated significant therapeutic effects of SZRD on diabetes and Alzheimer's disease (AD). However, the active ingredients and probable processes of SZRD in treating Alzheimer's with diabetes are unknown. This study aims to preliminarily elucidate the potential mechanisms and potential active ingredients of SZRD in the treatment of Alzheimer's with diabetes. METHODS: The main components and corresponding protein targets of SZRD were searched on the TCMSP database. Differential gene expression analysis for diabetes and Alzheimer's disease was conducted using the Gene Expression Omnibus database, with supplementation from OMIM and genecards databases for differentially expressed genes. The drug-compound-target-disease network was constructed using Cytoscape 3.8.0. Disease and SZRD targets were imported into the STRING database to construct a protein-protein interaction network. Further, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed on the intersection of genes. Molecular docking and molecular dynamics simulations were conducted on the Hub gene and active compounds. Gene Set Enrichment Analysis was performed to further analyze key genes. RESULTS: Through the Gene Expression Omnibus database, we obtained 1977 diabetes related genes and 622 AD related genes. Among drugs, diabetes and AD, 97 genes were identified. The drug-compound-target-disease network revealed that quercetin, kaempferol, licochalcone a, isorhamnetin, formononetin, and naringenin may be the core components exerting effects. PPI network analysis identified hub genes such as IL6, TNF, IL1B, CXCL8, IL10, CCL2, ICAM1, STAT3, and IL4. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that SZRD in the treatment of Alzheimer's with diabetes is mainly involved in biological processes such as response to drug, aging, response to xenobiotic, and enzyme binding; as well as signaling pathways such as Pathways in cancer, Chemical carcinogenesis - receptor activation, and Fluid shear stress and atherosclerosis. Molecular docking results showed that licochalcone a, isorhamnetin, kaempferol, quercetin, and formononetin have high affinity with CXCL8, IL1B, and CCL2. Molecular dynamics simulations also confirmed a strong interaction between CXCL8 and licochalcone a, isorhamnetin, and kaempferol. Gene Set Enrichment Analysis revealed that CXCL8, IL1B, and CCL2 have significant potential in diabetes. CONCLUSION: This study provides, for the first time, insights into the active ingredients and potential molecular mechanisms of SZRD in the treatment of Alzheimer's with diabetes, laying a theoretical foundation for future basic research.

The golden tickets: impact of preference signaling on obstetrics and gynecology residency applicants.

BACKGROUND: With the residency selection process becoming more competitive and programs receiving unprecedented numbers of applications, some specialties have introduced preference signaling in an attempt to help applicants target programs of interest. In the 2022-2023 application cycle, obstetrics and gynecology also introduced a 2-tiered system with a limited number of gold signals (n=3) and silver signals (n=15). OBJECTIVE: Given the novelty of preference signaling in the obstetrics and gynecology residency application process, this study aimed to (1) assess the effect of signals on interview offers and match and (2) discuss applicant attitudes toward this preference signaling system. STUDY DESIGN: This was a voluntary cross-sectional survey study conducted in April 2023 that was open to all fourth-year medical students who applied to an obstetrics and gynecology residency in the United States. Self-reported demographics, signaling, interview, and match data were collected. In addition, students were asked about attitudes toward signaling on a 5-point Likert scale. RESULTS: Of the 1507 applicants who entered an obstetrics and gynecology residency via match or Supplemental Offer and Acceptance Program process, 969 (64.3%) completed the survey. Moreover, an additional 22 applicants who did not match responded to the survey. More respondents used all 3 gold tokens (98.3%) and all 15 silver tokens (94.3%). The mean number of applications sent was 74.3±35.1, and the mean number of interviews received per applicant was 12.8±6.6. The interviews or token yields were 64.0%±31.5% for gold tokens, 43.8%±23.1% for silver tokens, and 9.8%±10.0% for no token. Of the survey respondents, 340/951 (35.8%) matched to a gold token program, 338/951 (35.5%) matched to a silver token program, and 244/951 (25.7%) matched to a nontoken program. Furthermore, 499/951 applicants (52.5%) reported feeling slightly positive or very positive about signaling. CONCLUSION: Most obstetrics and gynecology applicants in this survey participated in preference signaling. Gold and silver tokens were associated with high ratios of interview invitations compared with no token. However, the overall number of applications did not decrease in the 2022-2023 cycle, and only half of survey respondents reported feeling positive about the signaling process. These results can inform program directors and students about application number and strategy in upcoming cycles.

Hierarchical Surface Pattern on Ni-Free Ti-Based Bulk Metallic Glass to Control Cell Interactions.

Ni-free Ti-based bulk metallic glasses (BMGs) are exciting materials for biomedical applications because of their outstanding biocompatibility and advantageous mechanical properties. The glassy nature of BMGs allows them to be shaped and patterned via thermoplastic forming (TPF). This work demonstrates the versatility of the TPF technique to create micro- and nano-patterns and hierarchical structures on Ti40Zr10Cu34Pd14Sn2 BMG. Particularly, a hierarchical structure fabricated by a two-step TPF process integrates 400 nm hexagonal close-packed protrusions on 2.5 µm square protuberances while preserving the advantageous mechanical properties from the as-cast material state. The correlations between thermal history, structure, and mechanical properties are explored. Regarding biocompatibility, Ti40Zr10Cu34Pd14Sn2 BMGs with four surface topographies (flat, micro-patterned, nano-patterned, and hierarchical-structured surfaces) are investigated using Saos-2 cell lines. Alamar Blue assay and live/dead analysis show that all tested surfaces have good cell proliferation and viability. Patterned surfaces are observed to promote the formation of longer filopodia on the edge of the cytoskeleton, leading to star-shaped and dendritic cell morphologies compared with the flat surface. In addition to potential implant applications, TPF-patterned Ti-BMGs enable a high level of order and design flexibility on the surface topography, expanding the available toolbox for studying cell behavior on rigid and ordered surfaces.

Current Situation and Prospect of Adoptive Cellular Immunotherapy for Malignancies.

Adoptive cell immunotherapy (ACT) is an innovative promising treatment for tumors. ACT is characterized by the infusion of active anti-tumor immune cells (specific and non-specific) into patients to kill tumor cells either directly or indirectly by stimulating the body's immune system. The patient's (autologous) or a donor's (allogeneic) immune cells are used to improve immune function. Chimeric antigen receptor (CAR) T cells (CAR-T) is a type of ACT that has gained attention. T cells from the peripheral blood are genetically engineered to express CARs that rapidly proliferate and specifically recognize target antigens to exert its anti-tumor effects. Clinical application of CAR-T therapy for hematological tumors has shown good results, but adverse reactions and recurrence limit its applicability. Tumor infiltrating lymphocyte (TIL) therapy is effective for solid tumors. TIL therapy exhibits T cell receptor (TCR) clonality, superior tumor homing ability, and low targeted toxicity, but its successful application is limited to a number of tumors. Regardless, TIL and CAR-T therapies are effective for treating cancer. Additionally, CAR-natural killer (NK), CAR-macrophages (M), and TCR-T therapies are currently being researched. In this review, we highlight the current developments and limitations of several types of ACT.

Distance-Aware Learning for Inductive Link Prediction on Temporal Networks.

Inductive link prediction on temporal networks aims to predict the future links associated with node(s) unseen in the historical timestamps. Existing methods generate the predictions mainly by learning node representation from the node/edge attributes as well as the network dynamics or by measuring the distance between nodes on the temporal network structure. However, the attribute information is unavailable in many realistic applications and the structure-aware methods highly rely on nodes' common neighbors, which are difficult to accurately detect, especially in sparse temporal networks. Thus, we propose a distance-aware learning (DEAL) approach for inductive link prediction on temporal networks. Specifically, we first design an adaptive sampling method to extract temporal adaptive walks for nodes, increasing the probability of including the common neighbors between nodes. Then, we design a dual-channel distance measuring component, which simultaneously measures the distance between nodes in the embedding space and on the dynamic graph structure for predicting future inductive edges. Extensive experiments are conducted on three public temporal network datasets, i.e., MathOverflow, AskUbuntu, and StackOverflow. The experimental results validate the superiority of DEAL over the state-of-the-art baselines in terms of accuracy, area under the ROC curve (AUC), and average precision (AP), where the improvements are especially obvious in scenarios with only limited data.

A tunable broadband terahertz MoS2 absorber using series-parallel hybrid network design.

A method for designing a broadband absorber using a series-parallel hybrid network is proposed. The performance of the broadband absorber is improved by using frequency-selective surface patterns based on a series-parallel hybrid equivalent circuit. The results indicate that the tunable single-layered terahertz MoS2 absorber has excellent broadband characteristics. Between 0.84 and 2.34 THz, the absorption and relative absorption bandwidth exceed 90% and 94.3%, respectively. Also, the absorption level can be adjusted from 90% to 10% by applying a bias voltage on the electrodes. The effects of different types of MoS2 layers and surface fluctuations in monolayered MoS2 on the properties of the absorber are demonstrated. In the 60° (TM) and 50° (TE) ranges, the polarization of the terahertz absorber is insensitive to the incidence angle. Overall, this method enables the single-layered absorber to exhibit excellent broadband characteristics comparable to those of multilayered structures, as well as simplifies the structure. Consequently, this method significantly broadens the usefulness of tunable single-layered absorbers for radar stealth, terahertz imaging, and electrically tunable modulation.

The causality between gut microbiome and liver cirrhosis: a bi-directional two-sample Mendelian randomization analysis.

Background and aim: Previous studies have reported an association between gut microbiota and cirrhosis. However, the causality between intestinal flora and liver cirrhosis still remains unclear. In this study, bi-directional Mendelian randomization (MR) analysis was used to ascertain the potential causal effect between gut microbes and cirrhosis. Methods: Large-scale Genome Wide Association Study (GWAS) data of cirrhosis and gut microbes were obtained from FinnGen, Mibiogen consortium, and a GWAS meta-analysis of Alcoholic cirrhosis (ALC). Two-sample MR was performed to determine the causal relationship between gut microbiota and cirrhosis. Furthermore, a bi-directional MR analysis was employed to examine the direction of the causal relations. Result: In MR analysis, we found that 21 gut microbiotas were potentially associated with cirrhosis. In reverse MR analysis, 11 gut microbiotas displayed potentially associations between genetic liability in the gut microbiome and cirrhosis. We found that the family Lachnospiraceae (OR: 1.59, 95% CI:1.10-2.29) might be harmful in cirrhotic conditions (ICD-10: K74). Furthermore, the genus Erysipelatoclostridium might be a protective factor for cirrhosis (OR:0.55, 95% CI:0.34-0.88) and PBC (OR:0.68, 95% CI:0.52-0.89). Combining the results from the MR analysis and reverse MR analysis, we firstly identified the Genus Butyricicoccus had a bi-directional causal effect on PBC (Forward: OR: 0.37, 95% CI:0.15-0.93; Reverse: OR: 1.03, 95% CI:1.00-1.05). Conclusion: We found a new potential causal effect between cirrhosis and intestinal flora and provided new insights into the role of gut microbiota in the pathological progression of liver cirrhosis.

GlycoTCFM: Glycoproteomics Based on Two Complementary Fragmentation Methods Reveals Distinctive O-Glycosylation in Human Sperm and Seminal Plasma.

Human semen, consisting of spermatozoa (sperm) and seminal plasma, represents a special clinical sample type in human body fluid. Protein glycosylation in sperm and seminal plasma plays key roles in spermatogenesis, maturation, capacitation, sperm-egg recognition, motility of sperm, and fertilization. In this study, we profiled the most comprehensive O-glycoproteome map of human sperm and seminal plasma using our recently presented Glycoproteomics based on Two Complementary Fragmentation Methods (GlycoTCFM). We showed that sperm and seminal plasma contain many novel and distinctive O-glycoproteins, which are mostly located in the extracellular region (seminal plasma) and sperm membrane, enriched in the biological processes of cell adhesion and angiogenesis, and mainly involved in multiple biological functions including extracellular matrix structural constituents and binding. Based on GlycoTCFM, we created a comprehensive human sperm and seminal plasma O-glycoprotein database that contains 371 intact O-glycopeptides and 202 O-glycosites from 68 O-glycoproteins. Interestingly, 105 manually confirmed O-glycosites from 25 O-glycoproteins were reported for the first time, and they were mainly modified by core 1 O-glycans. We also found that three highly abundant, highly complex, and highly O-glycosylated proteins (semenogelin-1, semenogelin-2, and equatorin) may play important roles in sperm or seminal plasma composition and function. These data deepen our knowledge about O-glycosylation in sperm and seminal plasma and lay the foundation for the functional study of O-glycoproteins in male infertility.

Efficacy of CalliSpheres® microspheres versus conventional transarterial chemoembolization in the treatment of refractory colorectal cancer liver metastasis.

OBJECTIVE: CalliSpheres® is a microsphere that is already widely used for primary liver cancer treatment; however, its application in colorectal cancer liver metastasis (CRLM) is limited. The current study aimed to investigate the efficacy of CalliSpheres® drug-eluting bead (DEB) transarterial chemoembolization (TACE) therapy versus (vs.) conventional cTACE therapy in treating refractory CRLM (RCRLM) patients. METHODS: Twenty-two RCRLM patients who underwent CalliSpheres® DEB-TACE therapy (n = 11) or cTACE therapy (n = 11) were retrospectively analyzed. Data on clinical response, progression-free survival (PFS) and overall survival (OS) were retrieved. RESULTS: The objective response rate (36.4% vs. 18.2%, P = 0.338) and disease control rate (81.8% vs. 54.4%, P = 0.170) were both numerically (but not statistically) higher in the DEB-TACE group than in the cTACE group. Meanwhile, PFS was prolonged in the DEB-TACE group compared with the cTACE group [median: 12.0 (95% CI: 5.6-18.4) vs. 4.0 (95% CI: 0.9-7.1) months, P = 0.018]; OS was also longer in the DEB-TACE group compared with the cTACE group [median: 24.0 (95% CI: 18.3-29.7) vs. 14.0 (95% CI: 7.1-20.9) months, P = 0.040]. In addition, after adjustment by multivariate Cox analyses, DEB-TACE was superior to cTACE independently regarding PFS (HR: 0.110, 95% CI: 0.026-0.463, P = 0.003) and OS (HR: 0.126, 95% CI: 0.028-0.559, P = 0.006). CONCLUSION: CalliSpheres® DEB-TACE therapy may prolong survival profile than cTACE therapy in RCRLM patients, while further validation is still needed.

Does the Degree Matter? MD and DO Students Who Match Into OB/GYN Report Different Experiences in US Undergraduate Medical Education.

Background: Although allopathic (MD) and osteopathic (DO) students have similar curricular requirements, little is known about differences in MD and DO preparedness for obstetrics and gynecology (OB/GYN) residency. Objective: To assess differences in experiences and confidence of MD vs DO students who matched to OB/GYN. Methods: This cross-sectional survey study was open to all fourth-year medical students who matched to OB/GYN in the United States in April 2021. The survey included demographic data, clinical experiences, confidence (5-point sliding scale), and a 11-item knowledge test. Survey responses were compared to assess for disparities in experiences and confidence. Results: Survey response rate was 72.0% (1057 of 1469) students matched to OB/GYN postgraduate year 1 positions. Of the 871 MD and 175 DO responding students, MDs were more likely to have clerkships ≥6 weeks (78.1% vs 15.4%; P<.001) and a home sub-internship (92.0% vs 53.4%; P<.001). DOs reported more hands-on experiences with procedures (MD median=35 [20-35] vs DO median=40 [25-65]; P=.002). There was no difference in self-reported confidence in knowledge, technical skills, or having a realistic sense of internship, and no difference in baseline knowledge test scores. DOs felt less confident about their medical school preparation (aOR 0.40; 95% CI 0.25-0.66; P<.001) and were more likely to perceive inequity of residency preparation (aOR 1.88; 95% CI 1.18-3.00; P=.002). Conclusions: MD students matched to US OB/GYN residency programs reported longer clerkship and more home sub-internships, while DO students reported more hands-on experiences. Despite reporting similar confidence in knowledge and skills, DO students felt less prepared for internship.