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Annals of Surgical Oncology Jul 2024With nodal surveillance increasingly used for sentinel lymph node-positive (SLN+) melanoma following the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II),...
BACKGROUND
With nodal surveillance increasingly used for sentinel lymph node-positive (SLN+) melanoma following the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II), high-quality nodal ultrasonography (U/S) has become a critical need. Previous work has demonstrated low utilization of MSLT-II U/S criteria to define abnormal lymph nodes requiring intervention or biopsy. To address this gap, an evidence-based synoptic template was designed and implemented in this single-center study.
METHODS
Sentinel lymph node-positive patients undergoing nodal surveillance at a tertiary cancer center from July 2017 to June 2023 were identified retrospectively. Ultrasound reporting language was analyzed for MSLT-II criteria reported and clinically actionable recommendations (e.g., normal, abnormal with recommendation for biopsy). Following a multidisciplinary design process, the synoptic template was implemented in January 2023. Postimplementation outcomes were evaluated by using U/S reports and provider surveys.
RESULTS
A total of 337 U/S studies were performed on 94 SLN+ patients, with a median of 3 U/S per patient (range 1-12). Among 42 synoptic-eligible U/S performed postimplementation, 32 U/S (76.0%) were reported synoptically. Significant increases were seen in the number of MSLT-II criteria reported (Pre 0.5 ± 0.8 vs. Post 2.5 ± 1.0, p < 0.001), and clinically actionable recommendations for abnormal findings (Pre 64.0% vs. Post 93.0%, p = 0.04). Nearly all surgeon and radiologist survey respondents were "very" or "completely" satisfied with the clinical utility of the synoptic template (90.0%).
CONCLUSIONS
Following implementation of a synoptic template, U/S reports were significantly more likely to document MSLT-II criteria and provide an actionable recommendation, increasing usefulness to providers. Efforts to disseminate this synoptic template to other centers are ongoing.
PubMed: 38954095
DOI: 10.1245/s10434-024-15630-0 -
Molecular Diversity Jul 2024Proviral Integrations of Moloney-2 (PIM-2) kinase is a promising target for various cancers and other diseases, and its inhibitors hold potential for treating related...
Proviral Integrations of Moloney-2 (PIM-2) kinase is a promising target for various cancers and other diseases, and its inhibitors hold potential for treating related diseases. However, there is currently no clinically available PIM-2 inhibitor. In this study, we constructed a generative model for de novo PIM-2 inhibitor design based on artificial intelligence, performed molecular docking and molecular dynamics (MD) simulations to develop an efficient PIM-2 inhibitor generative model and discover potential PIM-2 inhibitors. First, we designed a generative model based on a Bi-directional Long Short-Term Memory (BiLSTM) framework combined with a transfer learning strategy and generated a new PIM-2 small molecule library using existing active drug databases. The generated compound library was then virtually screened by molecular docking and scaffold similarity comparison, identifying 10 initial hit compounds with better performance. Next, using the inhibitor in the crystal structure as a positive control, we performed two rounds of MD simulations, with lengths of 100 ns and 500 ns, respectively, to study the dynamic stability of the protein-ligand systems of the 10 compounds with PIM-2. Analyzed the interactions with key hinge region residues, binding free energies, and changes in the ATP pocket size. The generative model demonstrates good molecular generation capability and can generate efficient novel molecules with similar physicochemical properties as active PIM-2 drugs. Among the 10 initially selected hit compounds, 5 compounds C3 (- 29.69 kcal/mol), C4 (- 33.31 kcal/mol), C5 (- 28.59 kcal/mol), C8 (- 34.68 kcal/mol), and C9 (- 25.88 kcal/mol) have higher binding energies with PIM-2 than the positive drug 3YR (- 26.18 kcal/mol). The MD simulation results are consistent with the docking analysis, these compounds have lower and more stable RMSD values for the complex systems with the reported positive drug 3YR and PIM-2 complex system. They can form long-term stable interactions with active site and the hinge region of PIM-2, which suggests these compounds are likely to have potent inhibitory effects on PIM-2. This study provides an efficient generative model for PIM-2 inhibitor research and discovers 5 potential novel PIM-2 inhibitors.
PubMed: 38954072
DOI: 10.1007/s11030-024-10916-7 -
Antonie Van Leeuwenhoek Jul 2024A Gram-negative, rod-shaped, non-motile, aerobic bacterium, designated as strain TK19101, was isolated from the intermediate seawater of yellow vent in the shallow-sea...
A Gram-negative, rod-shaped, non-motile, aerobic bacterium, designated as strain TK19101, was isolated from the intermediate seawater of yellow vent in the shallow-sea hydrothermal system located near Kueishantao Island. The strain was found to grow at 10-40 °C (optimum, 35 °C), at pH 6.0-8.0 (optimum, 7.0), and in 0-5% (w/v) NaCl (optimum, 1%). Strain TK19101 was catalase-positive and oxidase-positive. The predominant fatty acids (> 10%) in strain TK19101 cells were C, summed feature 8 (C ω6c and/or C ω7c), and C. The predominant isoprenoid quinone of strain TK19101 was ubiquinone-10. The polar lipids of strain TK19101 comprised phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phospholipid, and unknown polar lipid. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain TK19101 belonged to the genus Mesobacterium. Strain TK19101 exhibited highest 16S rRNA gene sequence similarity value to Mesobacterium pallidum MCCC M24557 (97.48%). The estimated average nucleotide identity and digital DNA-DNA hybridization values between strain TK19101 and the closest related species Mesobacterium pallidum MCCC M24557 were 74.88% and 20.30%, respectively. The DNA G + C content was 63.49 mol%. On the basis of the analysis of 16S rRNA gene sequences, genotypic and phylogenetic data, strain TK19101 has a unique phylogenetic status and represents a novel species of genus Mesobacterium, for which the name Mesobacterium hydrothermale sp. nov. is proposed. The type strain is TK19101 (= MCCC 1K08936 = KCTC 8354).
Topics: Phylogeny; RNA, Ribosomal, 16S; Hydrothermal Vents; DNA, Bacterial; Fatty Acids; Seawater; Base Composition; Bacterial Typing Techniques; Islands; Phospholipids; Sequence Analysis, DNA; China
PubMed: 38954062
DOI: 10.1007/s10482-024-01994-6 -
Pediatric Surgery International Jul 2024To present the functional results after a transanal proximal rectosigmoidectomy in patients with severe idiopathic constipation in which medical treatment has failed.
PURPOSE
To present the functional results after a transanal proximal rectosigmoidectomy in patients with severe idiopathic constipation in which medical treatment has failed.
METHODS
Patients with severe idiopathic constipation who underwent transanal proximal rectosigmoidectomy (TPRS) at Children's Hospital Colorado between June 2019 and March 2024 were included in the study. We compared multiple pre- and post-operative outcome measures and the patient's bowel regimen before and after resection.
RESULTS
Fourteen patients underwent TPRS, 10 of whom were male. The average age at the time of surgery was 10.1 years (range 5-19). Seven patients have moderate to severe autism. Constipation-related clinic visits, family calls, procedural intervention, emergency room visits, and hospitalizations notably decreased frequency after TPRS. Laxative dosages and enema volume requirements were also reduced after surgery. Before surgery, all the patients suffered from daily fecal accidents, while post-operatively, all were completely free of stool accidents.
CONCLUSION
In our experience, for patients who suffer from severe medically refractory idiopathic constipation, TPRS has provided improvement in their symptoms and decreased the complications inherent to this chronic disease. Parents and patients attest to a profound positive transformation in their quality of life after surgery.
Topics: Humans; Constipation; Male; Female; Child; Adolescent; Child, Preschool; Rectum; Colon, Sigmoid; Young Adult; Treatment Outcome; Retrospective Studies; Quality of Life
PubMed: 38954056
DOI: 10.1007/s00383-024-05764-3 -
European Child & Adolescent Psychiatry Jul 2024Irritability is a common and clinically significant symptom associated with a wide range of negative outcomes. Ecological Momentary Assessment (EMA) is a valuable tool...
Irritability is a common and clinically significant symptom associated with a wide range of negative outcomes. Ecological Momentary Assessment (EMA) is a valuable tool for capturing experiences, such as emotions, social interactions, and substance use in real-time, and may be useful in understanding how irritability is related to everyday functioning. We investigated cross-sectional associations between a widely used self-report irritability rating scale and affect dynamics, social interactions, and substance use captured with EMA (5 surveys daily for 14 days) in 349 18-year-olds. We also examined the associations of self- and parent-reported irritability at ages 12 and 15 with the age 18 EMA variables to explore whether these relationships persist over time. Youth-reported irritability at age 18 was linked to greater intensity, variability, and inertia of irritability, sadness, and anxiety, less positive and more negative interpersonal experiences, and greater cigarette and drug use. Most effect sizes were in the medium-small range. Associations of youth- and parent-reported irritability at ages 12 and 15 with the age 18 EMA measures were generally similar, although smaller in magnitude. Findings contribute to understanding how irritability is manifested in real-time affect dynamics and interpersonal functioning, as well as daily substance use. Most effects were evident over the course of up to 6 years - that is, early adolescent irritability, reported by both youth and their parents, was associated with similar real-time affect dynamics and interpersonal experiences at age 18. This study contributes to the literature on the developmental psychopathology of irritability by extending findings to everyday functioning.
PubMed: 38954054
DOI: 10.1007/s00787-024-02504-9 -
GSDME-mediated pyroptosis promotes anti-tumor immunity of neoadjuvant chemotherapy in breast cancer.Cancer Immunology, Immunotherapy : CII Jul 2024Paclitaxel and anthracycline-based chemotherapy is one of the standard treatment options for breast cancer. However, only about 6-30% of breast cancer patients achieved...
Paclitaxel and anthracycline-based chemotherapy is one of the standard treatment options for breast cancer. However, only about 6-30% of breast cancer patients achieved a pathological complete response (pCR), and the mechanism responsible for the difference is still unclear. In this study, random forest algorithm was used to screen feature genes, and artificial neural network (ANN) algorithm was used to construct an ANN model for predicting the efficacy of neoadjuvant chemotherapy for breast cancer. Furthermore, digital pathology, cytology, and molecular biology experiments were used to verify the relationship between the efficacy of neoadjuvant chemotherapy and immune ecology. It was found that paclitaxel and doxorubicin, an anthracycline, could induce typical pyroptosis and bubbling in breast cancer cells, accompanied by gasdermin E (GSDME) cleavage. Paclitaxel with LDH release and Annexin V/PI doubule positive cell populations, and accompanied by the increased release of damage-associated molecular patterns, HMGB1 and ATP. Cell coculture experiments also demonstrated enhanced phagocytosis of macrophages and increased the levels of IFN-γ and IL-2 secretion after paclitaxel treatment. Mechanistically, GSDME may mediate paclitaxel and doxorubicin-induced pyroptosis in breast cancer cells through the caspase-9/caspase-3 pathway, activate anti-tumor immunity, and promote the efficacy of paclitaxel and anthracycline-based neoadjuvant chemotherapy. This study has practical guiding significance for the precision treatment of breast cancer, and can also provide ideas for understanding molecular mechanisms related to the chemotherapy sensitivity.
Topics: Breast Neoplasms; Humans; Pyroptosis; Female; Neoadjuvant Therapy; Mice; Animals; Paclitaxel; Doxorubicin; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Xenograft Model Antitumor Assays; Gasdermins
PubMed: 38954046
DOI: 10.1007/s00262-024-03752-z -
Cancer Immunology, Immunotherapy : CII Jul 2024Vulvar squamous cell carcinoma (VSCC) arises after an HPV infection or the mutation of p53 or other driver genes and is treated by mutilating surgery and/or (chemo)...
BACKGROUND
Vulvar squamous cell carcinoma (VSCC) arises after an HPV infection or the mutation of p53 or other driver genes and is treated by mutilating surgery and/or (chemo) radiation, with limited success and high morbidity. In-depth information on the immunological make up of VSCC is pivotal to assess whether immunotherapy may form an alternative treatment.
METHODS
A total of 104 patient samples, comprising healthy vulva (n = 27) and VSCC (n = 77), were analyzed. Multispectral immunofluorescence (15 markers) was used to study both the myeloid and lymphoid immune cell composition, and this was linked to differences in transcriptomics (NanoString nCounter, 1258 genes) and in survival (Kaplan-Meier analyses).
RESULTS
Healthy vulva and VSCC are both well infiltrated but with different subpopulations of lymphoid and myeloid cells. In contrast to the lymphoid cell infiltrate, the density and composition of the myeloid cell infiltrate strongly differed per VSCC molecular subtype. A relative strong infiltration with epithelial monocytes (HLADRCD11cCD14CD68CD163CD33) was prognostic for improved survival, independent of T cell infiltration, disease stage or molecular subtype. A strong infiltration with T cells and/or monocytes was associated with drastic superior survival: 5-year survival > 90% when either one is high, versus 40% when both are low (p < 0.001).
CONCLUSION
A hot myeloid and/or lymphoid infiltrate predicts excellent survival in VSCC. Based on the response of similarly high-infiltrated other tumor types, we have started to explore the potential of neoadjuvant checkpoint blockade in VSCC.
Topics: Humans; Female; Vulvar Neoplasms; Prognosis; Carcinoma, Squamous Cell; Biomarkers, Tumor; Monocytes; Middle Aged; Aged; Lymphocytes, Tumor-Infiltrating; Adult; Aged, 80 and over
PubMed: 38954042
DOI: 10.1007/s00262-024-03755-w -
Cancer Immunology, Immunotherapy : CII Jul 2024Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these...
Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial tumors due to relatively low toxicity and tumor specificity. Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice. Furthermore, vaccine-induced T cells were able to recognize and kill B16 cells after a short in vitro culture. Having found that glioblastoma multiforme (GBM) expresses significant levels of PD-L1 and IDO1, with PD-L1 correlating with poorer survival in patients with the mesenchymal subtype of GBM, we decided to combine SCIB1 ImmunoBody® with PD-1 immune checkpoint blockade to treat mice harboring intracranial tumors expressing TRP-2 and gp100. Time-to-death was significantly prolonged, and this correlated with increased CD4 and CD8 T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled.
Topics: Animals; Mice; Vaccines, DNA; Brain Neoplasms; Immune Checkpoint Inhibitors; Humans; Programmed Cell Death 1 Receptor; Cancer Vaccines; Mice, Inbred C57BL; Female; B7-H1 Antigen; Immunotherapy; Glioblastoma; Cell Line, Tumor; Intramolecular Oxidoreductases
PubMed: 38954031
DOI: 10.1007/s00262-024-03770-x -
Cancer Immunology, Immunotherapy : CII Jul 2024Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal...
BACKGROUND
Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal cancer (CRC) and their advantages remain unclear.
METHODS
Clinical data and specimens were used to evaluate the significance of CD103+CD8+ TRMs in CRC. A mouse subcutaneous tumorigenesis model and colony-formation assay were conducted to evaluate the anti-tumor effects of CD103+CD8+ TRMs. Finally, the infiltration density and function of CD103+CD8+ TRMs in the tumors were evaluated using flow cytometry.
RESULTS
In this study, we showed that highly infiltrated CD103+CD8+ TRMs were associated with earlier clinical stage and negative VEGF expression in CRC patients and predicted a favorable prognosis for CRC/CRC liver metastases patients. Interestingly, we also found that CD103+CD8+ TRMs may have predictive potential for whether CRC develops liver metastasis in CRC. In addition, we found a positive correlation between the ratio of the number of α-SMA+ vessels to the sum of the number of α-SMA+ and CD31+ vessels in CRC, and the infiltration level of CD103+CD8+ TRMs. In addition, anti-angiogenic therapy promoted infiltration of CD103+CD8+ TRMs and enhanced their ability to secrete interferon (IFN)-γ, thus further improving the anti-tumor effect. Moreover, in vivo experiments showed that compared with peripheral blood CD8+ T cells, CD103+CD8+ TRMs infused back into the body could also further promote CD8+ T cells to infiltrate the tumor, and they had a stronger ability to secrete IFN-γ, which resulted in better anti-tumor effects.
CONCLUSION
We demonstrated that CD103+CD8+ TRMs have the potential for clinical applications and provide new ideas for combined anti-tumor therapeutic strategies, such as anti-tumor angiogenesis therapy and CAR-T combined immunotherapy.
Topics: Colorectal Neoplasms; Integrin alpha Chains; Animals; Humans; CD8-Positive T-Lymphocytes; Mice; Liver Neoplasms; Antigens, CD; Prognosis; Female; Male; Immunologic Memory; Biomarkers, Tumor; Memory T Cells; Lymphocytes, Tumor-Infiltrating; Middle Aged
PubMed: 38954030
DOI: 10.1007/s00262-024-03709-2 -
Cancer Immunology, Immunotherapy : CII Jul 2024Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors,...
Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors, and soluble receptors in patients with CRC and cancer-free controls as possible CRC signatures. Serum levels of 65 analytes were measured in patients with CRC and age- and sex-matched cancer-free controls using the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Of the 65 tested analytes, 8 cytokines (CSF-3, IFN-γ, IL-12p70, IL-18, IL-20, MIF, TNF-α and TSLP), 8 chemokines (fractalkine, MIP-1β, BLC, Eotaxin-1, Eotaxin-2, IP-10, MIP-1a, MIP-3a), 2 growth factors (FGF-2, MMP-1), and 4 soluble receptors (APRIL, CD30, TNFRII, and TWEAK), were differentially expressed in CRC. ROC analysis confirmed the high association of TNF-α, BLC, Eotaxin-1, APRIL, and Tweak with AUC > 0.70, suggesting theranostic application. The expression of IFN-γ, IL-18, MIF, BLC, Eotaxin-1, Eotaxin-2, IP-10, and MMP1 was lower in metastatic compared to non-metastatic CRC; only AUC of MIF and MIP-1β were > 0.7. Moreover, MDC, IL-7, MIF, IL-21, and TNF-α are positively associated with tolerance to CRC chemotherapy (CT) (AUC > 0.7), whereas IL-31, Fractalkine, Eotaxin-1, and Eotaxin-2 were positively associated with resistance to CT. TNF-α, BLC, Eotaxin-1, APRIL, and Tweak may be used as first-line early detection of CRC. The variable levels of MIF and MIP-1β between metastatic and non-metastatic cases assign prognostic nature to these factors in CRC progression. Regarding tolerance to CT, MDC, IL-7, MIF, IL-21, and TNF-α are key when down-regulated or resistant to treatment is observed.
Topics: Humans; Colorectal Neoplasms; Female; Male; Cytokines; Middle Aged; Aged; Intercellular Signaling Peptides and Proteins; Chemokines; Treatment Outcome; Biomarkers, Tumor; Adult; Prognosis; Case-Control Studies
PubMed: 38954024
DOI: 10.1007/s00262-024-03746-x