Integrated chromosomal instability and tumor microbiome redefined prognosis-related subtypes of pancreatic cancer.

BACKGROUND: Pancreatic cancer is a common malignancy with poor prognosis and limited treatment. Here we aimed to investigate the role of host chromosomal instability (CIN) and tumor microbiome in the prognosis of pancreatic cancer patients. METHODS: One hundred formalin-fixed paraffin-embedded (FFPE) pancreatic cancer samples were collected. DNA extracted from FFPE samples were analyzed by low-coverage whole-genome sequencing (WGS) via a customized bioinformatics workflow named ultrasensitive chromosomal aneuploidy detector. RESULTS: Samples are tested according to the procedure of ultrasensitive chromosomal aneuploidy detector (UCAD). We excluded 2 samples with failed quality control, 1 patient lost to follow-up and 6 dead in the perioperative period. The final 91 patients were admitted for the following analyses. Thirteen (14.3%) patients with higher CIN score had worse overall survival (OS) than those with lower CIN score. The top 20 microbes in pancreatic cancer samples included 15 species of bacteria and 5 species of viruses. Patients with high human herpesvirus (HHV)-7 and HHV-5 DNA reads exhibited worse OS. Furthermore, we classified 91 patients into 3 subtypes. Patients with higher CIN score (n =13) had the worst prognosis (median OS 6.9 mon); patients with lower CIN score but with HHV-7/5 DNA load (n = 24) had worse prognosis (median OS 10.6 mon); while patients with lower CIN score and HHV-7/5 DNA negative (n = 54) had the best prognosis (median OS 21.1 mon). CONCLUSIONS: High CIN and HHV-7/5 DNA load were associated with worse survival of pancreatic cancer. The novel molecular subtypes of pancreatic cancer based on CIN and microbiome had prognostic value.

Two new oleanane triterpenes from Maytenus hookeri.

Two new triterpenes mayteneri A (1), mayteneri B (2), and seven known compounds (3-9) were isolated from stems of Maytenus hookeri Loes. The chemical structures of compounds 1 and 2 were established by 1D, 2D NMR, HRESIMS analysis, and calculating electronic circular dichroism (ECD). The structures of known compounds 3-9 were determined by comparison of their spectral with those reported. Compounds 4-7 showed significant inhibitory activity for NLRP3 inflammasome, with the IC50 values of 2.36-3.44 µM.

Abietane diterpenoids from Orthosiphon wulfenioides with NLRP3 inflammasome inhibitory activity.

Wulfenioidones A - K (1-11) were abietane diterpenoids with highly oxidized 6/6/6 aromatic tricyclic skeleton isolated from the whole plant of Orthosiphon wulfenioides, and their planar structures and absolute configurations were elucidated by spectroscopic data interpretation, electronic circular dichroism calculation as well as X-ray crystallography analysis. Bioactivity screening indicated that compounds 1-4, 6 and 8 exhibited lactate dehydrogenase (LDH) inhibition effect with IC50 values ranging from 0.23 to 3.43 µM by preventing the mononuclear macrophage cell pyroptosis induced by double signal stimulation of LPS and nigericin. Western Blot analyses of Caspase-1 and IL-1ß down-regulation exhibited that compound 1 could selectively inhibit NLRP3 inflammasome, and the cell morphological observation further supported that compound 1 prevented macrophage cell pyroptosis.

Association between self-disclosure and benefit finding of Chinese cancer patients caregivers: the mediation effect of coping styles.

PURPOSE: To examine the relationship between self-disclosure, coping styles, and benefit finding (BF) among caregivers of cancer patients. The study also aimed to identify the factors influencing BF and the impact of coping styles on the relationship between self-disclosure and BF. METHODS: Convenience sampling was used to select 300 caregivers of cancer patients aged greater than 18 years from October 2022 to April 2023 in Chengdu, China. The demographic and clinical characteristics questionnaire, the Benefit Finding Scale (BFS), the Distress Disclosure Index Scale (DDI), and the Simple Coping Style Scale (SCSQ) for caregivers were included in this study. Descriptive statistics, t-tests, one-way analysis of variance, Pearson's correlation analyses, and multiple linear regression models were used. The effect of mediation was tested by the PROCESS macro (Model 4) for SPSS 26.0 by Hayes using 5000 bootstrap samples. RESULTS: There were 292 valid questionnaires (effective response rate 97.33%). The total scores of BF, self-disclosure, negative coping style, and positive coping style of caregivers were 67.77 ± 14.78, 38.23 ± 8.59, 19.68 ± 5.98, and 9.88 ± 4.18, respectively; Pearson's correlation analysis showed that BF was positively correlated with self-disclosure, positive coping, and negatively correlated with negative coping; multiple linear regression analysis showed that self-disclosure, positive coping, and negative coping were influential factors of BF. The results revealed that the effect of self-disclosure on BF was partly mediated by coping styles. It also confirmed that the mediation effect accounted for 54.03% of the total effect. CONCLUSION: The BF of caregivers is at a moderate level. Self-disclosure may influence BF partly because of coping styles.

Chemical Constituents of the Branches and Leaves of Picrasma chinensis P.Y. Chen and Tyrosinase Inhibiting Activity.

One new alkaloid, picrasine A, two new quassinoids, picralactones A-B, together with eleven known compounds were isolated from Picrasma chinensis P.Y. Chen. The structures of these compounds were determined using 1D and 2D NMR, HR-ESI-MS, and IR spectroscopic data, and by comparison with published data. Some compounds were tested for tyrosinase inhibiting activity, however, none of them exhibited strong inhibitory effects.

Highly Oxygenated Labdane Diterpenoids from Stevia rebaudiana and Their Anti-Atherosclerosis Activities.

Five unknown labdane diterpenoids Stevelins A-E (1-5), three known labdane diterpenoids (6-8) and three labdane norditerpenoids (9-11) were isolated from the Stevia rebaudiana. The structures were determined primarily via NMR spectroscopic data and HR-ESI-MS experiments. X-ray crystallography using CuKα radiation was used to determine the absolute configurations of 1, and the absolute configurations of 2-5 were deduced by electronic circular dichroism (ECD) calculations. The potential anti-atherosclerosis activities of all compounds were evaluated by measuring their inhibitory effects on the macrophage foam cell formation. As a result, most isolated compounds could significantly inhibit oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation, which suggests that these compounds may be promising candidates in the treatment for atherosclerosis.

Callicarpanes A-L, Twelve New Clerodane Diterpenoids with NLRP3 Inflammasome Inhibitory Activity from Callicarpa integerrima.

Twelve new clerodane diterpenoids named callicarpanes A-L (1-12), together with eight known compounds (13-20), were isolated from Callicarpa integerrima. Their structures were determined by comprehensive spectroscopic data. The calculated chemical shifts were used to identify relative configurations using DP4+ analysis. The absolute configurations (AC) were assigned based on quantum chemical calculations and X-ray single-crystal diffraction methods. Compounds 1, 3, 5, 9, 10, 12, 15, 16, and 19 showed significant inhibitory activity for NLRP3 inflammasome activation, with the IC50 against lactate dehydrogenase (LDH) release ranging from 0.08 to 4.78 µM. Further study revealed that compound 10 repressed IL-1ß secretion and caspase-1 maturation in J774A.1 cell as well as blocked macrophage pyroptosis.

Chemical constituents from the twigs and leaves of Picrasma quassioides.

Two new compounds, including a norsesquiterpenoid, annuionone H (1), and a quassinoid, picraqualide G (2), along with eleven known compounds (3-13), were isolated from the twigs and leaves of Picrasma quassioides. Comprehensive spectroscopic analyses and NMR calculation with DP4+ analysis were used to identify their structures. Moreover, of all these compounds, compound 4 showed a week inhibition rate in the anti-inflammatory screening results against mouse macrophage J774A.1 cell.

Two new compounds from Verbena bonariensis.

Two new compounds verboncin A (1) and verboncin B (4) and 14 known compounds (2-3 and 5-16) were isolated from Verbena bonariensis, and these 14 compounds were first obtained from this plant. Their chemical structures were established by one and two-dimensional NMR and HRESIMS analysis and the results were compared with literature values. The absolute configuration of 1 was determined by calculating electronic circular dichroism (ECD). The cytotoxicity of some of the compounds against MCF-7, HCT-116, MDA-MB-231, and SW620 human cancer cell lines were evaluated, in which compound 4 showed negligible cytotoxic activity with an IC50 value of 68.08 ± 0.35 µM against the MCF-7 cell line.

Opioid-Sparing Pain Control after Rhinoplasty: Updated Review of the Literature.

Rhinoplasty is one of the most performed elective surgeries, and given the opioid crisis, increasing research and studies are focused on successful pain control with multimodality opioid-sparing techniques, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and gabapentin. Although limiting overuse of opioids is critical, this cannot be at the expense of inadequate pain control, particularly as insufficient pain control can be correlated with patient dissatisfaction and the postoperative experience in elective surgery. There is likely significant opioid overprescription, as patients often report taking less than 50% of their prescribed opioids. Furthermore, excess opioids provide opportunities for misuse and opioid diversion if not disposed of properly. To optimize postoperative pain control and minimize opioid requirements, interventions must occur at the preoperative, intraoperative, and postoperative time points. Preoperative counseling is imperative to set expectations for pain and to screen for predisposing factors for opioid misuse. Intraoperatively, use of local nerve blocks and long-acting analgesia in conjunction with modified surgical techniques can lead to prolonged pain control. Postoperatively, pain should be managed with a multimodal approach, incorporating acetaminophen, NSAIDs, and potentially gabapentin with opioids reserved for rescue analgesia. Rhinoplasty represents a category of short-stay, low/medium pain, and elective procedures highly susceptible to overprescription and consequently, are readily amenable to opioid minimization through standardized perioperative interventions. Recent literature on regimens and interventions to help limit opioids after rhinoplasty are reviewed and discussed here.

Health Utility Measures Among Patients with Androgenetic Alopecia After Hair Transplant.

BACKGROUND: Hair loss causes significant psychosocial distress to patients. Health utility measurements offer an objective, quantitative assessment of health-related quality of life (QOL). METHODS: We performed a prospective cohort study on patients with hair loss between January 1, 2018 and December 31, 2020. Patient metrics were compared with layperson perception of alopecia, prospectively collected between August 1 and December 31, 2017. Health utility measures were quantified using the visual analog scale (VAS), standard gamble (SG), and time trade-off (TTO) in quality-adjusted life-years (QALYs) and relative to the minimal clinically important difference (MCID). Bonferroni correction to the significance threshold was performed. RESULTS: Thirty-one patients with alopecia were compared with 237 laypeople. Patient metrics for female hair loss were all significantly lower than laypeople measures (VAS QALYs 0.65 ± 0.21 vs. 0.83 ± 0.18, p = 0.0001). Mean SG QALYs were lower for patients in the male alopecia state (0.86 ± 0.23 vs. 0.96 ± 0.12, p = 0.0278). Post-hair transplant improvement in TTO was significantly greater for patients (+ 0.08 ± 0.12 vs. + 0.02 ± 0.09, p = 0.0070) and significantly more often exceeded the MCID (45.2% vs. 16.9%, p = 0.0006). CONCLUSIONS: Alopecia negatively impacts QOL, and the true patient experience is more taxing than what is perceived by laypeople. Hair transplantation improves QOL more for male patients than common perception. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Sinomenine Hydrochloride Can Ameliorate Benign Prostatic Hyperplasia by Lowering the 5α-Reductase 2 Level and Regulating the Balance between the Proliferation and Apoptosis of Cells.

Benign prostatic hyperplasia (BPH) is a chronic disease that affects the quality of life of older males. Sinomenine hydrochloride (SIN) is the major bioactive alkaloid isolated from the roots of the traditional Chinese medicinal plant Sinomenium acutum Rehderett Wilson. We wondered if the SIN administration exerted a regulatory effect on BPH and its potential mechanism of action. Mice with testosterone propionate-induced BPH subjected to bilateral orchiectomy were employed for in vivo experiments. A human BPH cell line (BPH-1) was employed for in vitro experiments. SIN administration inhibited the proliferation of BPH-1 cells (p < 0.05) by regulating the expression of androgen-related proteins (steroid 5-alpha reductase 2 (SRD5A2), androgen receptors, prostate-specific antigen), apoptosis-related proteins (B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax)) and proliferation-related proteins (proliferating cell nuclear antigen (PCNA), mammalian target of rapamycin, inducible nitric oxide synthase) in vitro. SIN administration decreased the prostate-gland weight coefficient (p < 0.05) and improved the histological status of mice suffering from BPH. The regulatory effects of SIN administration on SRD5A2, an apoptosis-related protein (Bcl-2), and proliferation-related proteins (PCNA, matrix metalloproteinase-2) were consistent with in vitro data. SIN exerted a therapeutic effect against BPH probably related to lowering the SRD5A2 level and regulating the balance between the proliferation and apoptosis of cells. Our results provide an important theoretical basis for the development of plant medicines for BPH therapy.

Roseicella aquatilis sp. nov., isolated from freshwater lake.

A novel Gram-stain-negative, non-motile, ellipsoidal-shaped, red-pigmented, facultatively aerobic strain designated NE82T was isolated from mud sample from Jiugongli Lake in Inner Mongolia Autonomous Region, China. Optimal growth occurred at 28-33 °C (range 15-42 °C) and pH 7.0-7.5 (range 5.5-8.5) with 0% (w/v) NaCl (range 0-1.0%). Cells of strain NE82T were 0.4-0.9 µm in diameter, catalase-positive and oxidase-negative. Q-10 was the sole respiratory quinone and the major cellular fatty acids (> 10%) in strain NE82T were summed feature 8 (C18:1 ω7c and C18:1 ω6c). The polar lipids of strain NE82T were phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, an unidentified aminophospholipid and four unidentified phospholipids. The G+C content of the genomic DNA was 72.0 mol%. Based on the 16S rRNA gene sequence, strain NE82T showed the highest similarity (97.2%) to Roseicella frigidaeris DB1506T within the family Acetobacteraceae, thus representing a novel species of the genus Roseicella, for which the name Roseicella aquatilis sp. nov. is proposed. The type strain is NE82T (= KCTC 62412T = MCCC 1H00292T).

Design, synthesis and anti-breast cancer evaluation of biaryl pyridine analogues as potent RSK inhibitors.

In order to discover and develop the new RSK kinase inhibitor, 50 pyridyl biaryl derivatives were designed and synthesized with LJH685 as the lead compound and their anti-tumor ability was tested. The results showed that the ability of 7d compound to inhibit the phosphorylation of YB-1 was comparable to that of LJH685. Among them, after preliminary screening, compound 7d showed good activity in inhibiting cell proliferation. Therefore, we took 7d as an example and performed molecular docking analysis on it. Judging from the overlapping combination diagram with LJH685, the results have verified that compound 7d has a similar skeleton to LJH685 and has a similar docking effect with RSK. Therefore, compound 7d is in line with the RSK inhibitor we designed and could be developed to a promising anti-tumor drug in the future.

Spiroarborin, an ent-Clerodane Homodimer from Callicarpa arborea as an Inhibitor of the Eleven-Nineteen Leukemia (ENL) Protein by Targeting the YEATS Domain.

A spiro ent-clerodane homodimer with a rare 6/6/6/6/6-fused pentacyclic scaffold, spiroarborin (1), together with four new monomeric analogues (2-5), were isolated from Callicarpa arborea. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum-chemical calculations, and X-ray diffraction. A plausible biosynthetic pathway of 1 was proposed, and a biomimetic synthesis of its derivative was accomplished. Compound 1 showed a potent inhibitory effect by directly binding to the YEATS domain of the 11-19 leukemia (ENL) protein with an IC50 value of 7.3 µM. This gave a KD value of 5.0 µM, as recorded by a surface plasmon resonance binding assay.

Callintegers A and B, Unusual Tricyclo[4.4.0.09,10]tetradecane Clerodane Diterpenoids from Callicarpa integerrima with Inhibitory Effects on NLRP3 Inflammasome Activation.

Callintegers A (1) and B (2), unprecedented clerodane norditerpenoids based on a novel carbon skeleton, were isolated from Callicarpa integerrima. Compounds 1 and 2 possess a novel 6/6/6-fused tricyclic ring system. Their structures and absolute configurations were determined by quantum chemical calculations, spectroscopic analysis, and single-crystal X-ray diffraction methods. Biological evaluation showed that compound 2 inhibited IL-1ß secretion in a dose-dependent manner with an IC50 value of 5.5 ± 3.2 µM. Caspase-1 maturation and IL-1ß secretion were also reduced, indicating that compound 2 impaired NLRP3 inflammasome activation.

The discovery of potentially active diterpenoids to inhibit the pyroptosis from Callicarpa arborea.

Pyroptosis is a programmed-inflammatory cell death, which leads to release of inflammatory cellular contents and formation of inflammation. Uncontrollable pyroptosis can result in serious immune diseases, such as cytokine release syndrome (CRS), sepsis, disseminated intravascular coagulation (DIC), and acute organ damage, including acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Members of the Callicarpa genus are significant raw materials for traditional Chinese medicine, widely used for analgesia, hemostasis, and anti-inflammation. Previously, we have reported some ent-clerodane diterpenoids from Callicarpa arborea, shown potent inhibitory effects against pyroptosis. In this study, we went on investigating this kind of diterpenoids, and yielded 66 ent-clerodane diterpenoids, including 52 new compounds, from Callicarpa arborea. Their structures featured with a 5/6- (1-25) or a 6/6- (26-66)-fused double-ring scaffolds, were elucidated using spectroscopic data, electrostatic circular dichroism (ECD) and X-ray diffraction analyses. Screening for the inhibitory activity against pyroptosis by detecting of IL-1ß secretion in J771A.1 cells, revealed 28 compounds with an IC50 below 10.5 µM. Compound 1 was the most potent with an IC50 of 0.68 µM and inhibited the J774A.1 macrophage pyroptosis by blocking the NLR pyrin domain containing 3 (NLRP3) inflammasome activation. An in vivo study further revealed that compound 1 decreased infiltration of CD11b + F4/80 + macrophages into lung and attenuated the lipopolysaccharide (LPS)-induced lung injury. Taken together, this study indicated the potential of compound 1 as a candidate for pyroptosis-related inflammation treatment, as well as provided the chemical and pharmacological basis for the further development of Callicarpa genus as a herbal medicine.

Callicarpnoids A-C, structurally intriguing ent-Clerodane diterpenoid dimers with cytotoxicity against MCF-7 and HCT-116 cell lines from Callicarpa arborea Roxb.

Callicarpnoids A-C (1-3), three new ent-clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with IC50 ranging from 5.2 to 7.2 µM, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bcl2 were decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells.

cGAS and cancer therapy: a double-edged sword.

Cyclic guanosine monophosphate-adenosine monophosphate adenosine synthetase (cGAS) is a DNA sensor that detects and binds to cytosolic DNA to generate cyclic GMP-AMP (cGAMP). As a second messenger, cGAMP mainly activates the adapter protein STING, which induces the production of type I interferons (IFNs) and inflammatory cytokines. Mounting evidence shows that cGAS is extensively involved in the innate immune response, senescence, and tumor immunity, thereby exhibiting a tumor-suppressive function, most of which is mediated by the STING pathway. In contrast, cGAS can also act as an oncogenic factor, mostly by increasing genomic instability through inhibitory effects on DNA repair, suggesting its utility as an antitumor target. This article reviews the roles and the underlying mechanisms of cGAS in cancer, particularly focusing on its dual roles in carcinogenesis and tumor progression, which are probably attributable to its classical and nonclassical functions, as well as approaches targeting cGAS for cancer therapy.

Recommendations for improving the working conditions and cultures of distressed junior doctors, based on a qualitative study and stakeholder perspectives.

BACKGROUND: Doctors, including junior doctors, are vulnerable to greater levels of distress and mental health difficulties than the public. This is exacerbated by their working conditions and cultures. While this vulnerability has been known for many years, little action has been taken to protect and support junior doctors working in the NHS. As such, we present a series of recommendations from the perspective of junior doctors and other relevant stakeholders, designed to improve junior doctors' working conditions and, thus, their mental health. METHODS: We interviewed 36 junior doctors, asking them for recommendations for improving their working conditions and culture. Additionally, we held an online stakeholder meeting with a variety of healthcare professionals (including junior doctors), undergraduate medical school leads, postgraduate speciality school leads and NHS policymakers where we asked what could be done to improve junior doctors' working conditions. We combined interview data with notes from the stakeholder discussions to produce this set of recommendations. RESULTS: Junior doctor participants and stakeholders made organisational and interpersonal recommendations. Organisational recommendations include the need for more environmental, staff and educational resources as well as changes to rotas. Interpersonal recommendations include changes to communication and recommendations for better support and teamwork. CONCLUSION: We suggest that NHS policymakers, employers and managers consider and hopefully implement the recommendations set out by the study participants and stakeholders as reported in this paper and that the gold standards of practice which are reported here (such as examples of positive learning environments and supportive supervision) are showcased so that others can learn from them.