Construction of a nomogram with IrAE and clinic character to predict the survival of advanced G/GEJ adenocarcinoma patients undergoing anti-PD-1 treatment.

Objective: This study aimed to develop and validate a survival prediction model and nomogram to predict survival in patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma undergoing treatment with anti-programmed cell death 1 receptor (PD-1). This model incorporates immune-related adverse events (irAEs) alongside common clinical characteristics as predictive factors. Method: A dataset comprising 255 adult patients diagnosed with advanced G/GEJ adenocarcinoma was assembled. The irAEs affecting overall survival (OS) to a significant degree were identified and integrated as a candidate variable, together with 12 other candidate variables. These included gender, age, Eastern cooperative oncology group performance status (ECOG PS) score, tumor stage, human epidermal growth factor receptor 2 (HER2) expression status, presence of peritoneal and liver metastases, year and line of anti-PD-1 treatment, neutrophil-to-lymphocyte ratio (NLR), controlling nutritional status (CONUT) score, and Charlson comorbidity index (CCI). To mitigate timing bias related to irAEs, landmark analysis was employed. Variable selection was performed using the least absolute shrinkage and selection operator (LASSO) regression to pinpoint significant predictors, and the variance inflation factor was applied to address multicollinearity. Subsequently, a Cox regression analysis utilizing the forward likelihood ratio method was conducted to develop a survival prediction model, excluding variables that failed to satisfy the proportional hazards (PH) assumption. The model was developed using the entire dataset, then internally validated through bootstrap resampling and externally validated with a cohort from another Hospital. Furthermore, a nomogram was created to delineate the predictive model. Results: After consolidating irAEs from the skin and endocrine systems into a single protective irAE category and applying landmark analysis, variable selection was conducted for the prognostic prediction model along with other candidate variables. The finalized model comprised seven variables: ECOG PS score, tumor stage, HER2 expression status in tumor tissue, first-line anti-PD-1 treatment, peritoneal metastasis, CONUT score, and protective irAE. The overall concordance index for the model was 0.66. Calibration analysis verified the model's accuracy in aligning predicted outcomes with actual results. Clinical decision curve analysis indicated that utilizing this model for treatment decisions could enhance the net benefit regarding 1- and 2-year survival rates for patients. Conclusion: This study developed a prognostic prediction model by integrating common clinical characteristics of irAEs and G/GEJ adenocarcinoma. This model exhibits good clinical practicality and possesses accurate predictive ability for overall survival OS in patients with advanced G/GEJ adenocarcinoma.

Pretreatment pulmonary tumor necrosis is a promising prognostic imaging biomarker for first-line anti-PD-1/PD-L1 therapy in advanced lung squamous cell carcinoma: a multi-institutional, propensity score-matching cohort analysis.

Background: Tumor necrosis (TN) is a common feature in lung squamous cell carcinoma (LSCC), which could provide useful predictive and prognostic information. Objectives: This study aimed to investigate the effect of pretreatment pulmonary TN (PTN) on the prognosis of first-line anti-programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) inhibitor in advanced LSCC. Design: We conducted a retrospective study to analyze the association between the presence of PTN and clinical outcomes in advanced LSCC patients treated with anti-PD-1/PD-L1 inhibitors. Methods: Data from 240 eligible patients were collected from 27 hospitals across China between 2016 and 2020. The presence of PTN was assessed using contrast-enhanced chest computed tomography (CT) imaging at baseline. We utilized the Cox proportional-hazards regression model to analyze the association between PTN and clinical outcomes. In addition, to account for potential confounding factors and ensure comparability between groups, we employed propensity score-matching (PSM) analysis. Results: In the overall patient cohort, the presence of PTN was 39.6%. The median follow-up duration was 20.3 months. The positive PTN group exhibited a notably inferior median progression-free survival (PFS; 6.5 months vs 8.6 months, p = 0.012) compared to the negative PTN group. Within the Cox proportional-hazards regression model, PTN emerged as an independent predictor of unfavorable PFS (hazard ratio (HR) = 1.354, 95% confidence interval (CI): 1.002-1.830, p = 0.049). After PSM, the median PFS for the positive PTN group (6.5 months vs 8.0 months, p = 0.027) remained worse than that of the negative PTN group. Multivariate analyses also further underscored that the presence of PTN independently posed a risk for shorter PFS (HR = 1.494, 95% CI: 1.056-2.112, p = 0.023). However, no statistically significant difference in overall survival was observed between the two groups. Conclusion: Our study suggests that the presence of PTN on baseline contrast-enhanced chest CT is a potential negative prognostic imaging biomarker for the outcome of anti-PD-1/PD-L1 inhibitor therapy in advanced LSCC. Further studies are warranted to validate these findings and explore the underlying mechanisms.

Predicting anti-PD-1/PD-L1 inhibitor treatment outcomes: pulmonary tumor necrosis in lung squamous cell carcinoma Our study focused on lung squamous cell carcinoma (LSCC) patients receiving first-line anti-PD-1/PD-L1 therapy. We explored the impact of a feature called pretreatment pulmonary tumor necrosis (PTN) on their prognosis. PTN was identified in 39.6% of patients using baseline chest CT scans. Results revealed that patients with PTN had a shorter time without disease progression (median PFS of 6.5 months compared to 8.6 months) and a higher risk of unfavorable outcomes. This suggests that PTN may serve as a negative prognostic imaging marker for anti-PD-1/PD-L1 therapy in advanced LSCC. Further research is needed to confirm and understand these findings better.

A two-stage maintenance trial of cetuximab-based treatment in RAS and BRAF wild-type unresectable metastatic colorectal cancer: a retrospective real-world study.

Background: To investigate the effectiveness and safety of maintenance regimens based on cetuximab, we conducted a real-world, single-arm, retrospective study at a single center. Methods: In Fujian Medical University Union Hospital, patients with unresectable metastatic colorectal cancer (mCRC) who received cetuximab-based maintenance therapy between December 2020 and December 2021 were included. All patients had RAS and BRAF wild-type. The maintenance regimen consisted of 6-12 cycles of cetuximab plus irinotecan (Phase 1) and cetuximab (Phase 2). Patients could receive reintroduction therapy in case of disease progression during Phase 2. Progression-free survival (PFS), overall survival (OS), and safety data were collected. Results: According to the inclusion and exclusion criteria of the study, a total of 108 subjects who received maintenance therapy were included- 51 experienced disease progression during Phase 1, with PFS (1) of 7.3 months. Among the 52 patients who entered Phase 2, 17 were still in this phase at the end of follow-up, with PFS (2) of 10.1 months. In Phase 2, 35 patients experienced disease progression, of whom 24 received reintroduction therapy, with PFS (3) of 6.7 months. The overall PFS (total) during the maintenance period was 11.9 months, and the OS was 39.2 months. Grade III or higher adverse events were 4.6% during Phase 1 and 0% during Phase 2. Conclusion: Innovative cetuximab-based maintenance therapy showed a trend toward improving the prognosis of mCRC patients with RAS and BRAF wild-type, while the toxic side effects of maintenance therapy were manageable. Clinical trial registration: https://www.chictr.org.cn, identifier ChiCTR2000040940.

Determination of the effective dose of remimazolam combined with sufentanil for inhibiting body movement during surgical abortion: An up-and-down sequential allocation trial.

BACKGROUND: Remimazolam, a recently developed anesthetic characterized by its rapid and ultra-short-acting properties, exhibits pharmacological attributes that make it potentially suitable for painless surgical abortion procedures. The objective of this study was to determine the effective dose of remimazolam when administered in combination with sufentanil, with the intention of inhibiting body movement during surgical abortion. Additionally, a secondary objective was to assess the recovery profile from general anesthesia. METHODS: The study enrolled a total of 25 healthy women aged 20 to 40, with a body mass index between 18 and 28 kg/m2, in their first trimester of pregnancy (up to 12 weeks), and American Society of Anesthesiologists status I and II. Anesthesia induction was initiated by administering sufentanil at a dose of 0.1 µg/kg. The modified Dixon up-and-down method was employed to determine the induction dose of remimazolam for each patient. RESULTS: The 50% and 95% effective dose of remimazolam for inhibitory effects of body movement was estimated using centered isotonic regression to be 0.145 mg/kg (95% CI: 0.115, 0.207), and 0.242 mg/kg (95% CI: 0.232, 0.620), respectively. Five out of 25 (20%) experienced hiccups, with 1 patient having persistent hiccups until the end of the surgery. The mean time to first eye-opening was 51.4 ±â€…20.5 seconds, and the time to obey verbal command was 54.5 ±â€…20.6 seconds. Upon arrival at the postanesthesia care unit, 95.7% of the patients achieved a Modified Aldrete score ≥ 9. CONCLUSIONS: The 50% and 95% effective dose of remimazolam for inhibiting body movement during surgical abortion when used in combination with 0.1 µg/kg of sufentanil were 0.145 mg/kg and 0.242 mg/kg, respectively.

A fluorinated metal-organic framework-based quasi-solid electrolyte for stabilizing Li metal anodes.

A fluorinated quasi-solid electrolyte (QSE) with a high conductivity of 2.3 mS cm-1 is meticulously designed for Li metal batteries. It facilitates the formation of a LiF-rich solid electrolyte interface that effectively enhances the reversibility of Li anodes. The assembled Li|QSE|LiFePO4 batteries exhibit 92.3% capacity retention after 1500 cycles and an impressive capacity of up to 45 mA h g-1 at 20C.

The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells.

BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.

Penpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study.

Penpulimab is an anti-programmed cell death-1 (PD-1) IgG1 antibody with no Fc gamma receptor (FcγR) binding activity, and thus theoretically reduced immune-related adverse events (irAEs) while maintaining efficacy. This single-arm, phase II trial conducted across 20 tertiary care centers in China enrolled adult patients with metastatic nasopharyngeal carcinoma (NPC) who had failed two or more lines of previous systemic chemotherapy. Patients received 200-mg penpulimab intravenously every 2 weeks (4 weeks per cycle) until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST (version 1.1), as assessed by an independent radiological review committee. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). One hundred thirty patients were enrolled and 125 were efficacy evaluable. At the data cutoff date (September 28, 2022), 1 patient achieved complete response and 34 patients attained partial response. The ORR was 28.0% (95% CI 20.3-36.7%). The response was durable, with 66.8% still in response at 9 months. Thirty-three patients (26.4%) were still on treatment. The median PFS and OS were 3.6 months (95% CI = 1.9-7.3 months) and 22.8 months (95% CI = 17.1 months to not reached), respectively. Ten (7.6%) patients experienced grade 3 or higher irAEs. Penpulimab has promising anti-tumor activities and acceptable toxicities in heavily pretreated metastatic NPC patients, supporting further clinical development as third-line treatment of metastatic NPC.

A "Zn2+ in Salt" Interphase Enabling High-Performance Zn Metal Anodes.

Zinc metal is a promising anode candidate for aqueous zinc ion batteries due to its high theoretical capacity, low cost, and high safety. However, its application is currently restricted by hydrogen evolution reactions (HER), by-product formation, and Zn dendrite growth. Herein, a "Zn2+ in salt" (ZIS) interphase is in situ constructed on the surface of the anode (ZIS@Zn). Unlike the conventional "Zn2+ in water" working environment of Zn anodes, the intrinsic hydrophobicity of the ZIS interphase isolates the anode from direct contact with the aqueous electrolyte, thereby protecting it from HER, and the accompanying side reactions. More importantly, it works as an ordered water-free ion-conducting medium, which guides uniform Zn deposition and facilitates rapid Zn2+ migration at the interface. As a result, the symmetric cells assembled with ZIS@Zn exhibit dendrite-free plating/striping at 4500 h and a high critical current of 14 mA cm-2. When matched with a vanadium-based (NVO) cathode, the full battery exhibits excellent long-term cycling stability, with 88% capacity retention after 1600 cycles. This work provides an effective strategy to promote the stability and reversibility of Zn anodes in aqueous electrolytes.

Cannabinoid CB2 receptors in primary sensory neurons are implicated in CB2 agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance.

Cannabinoid CB2 agonists show therapeutic efficacy without unwanted CB1-mediated side effects. The G protein-biased CB2 receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated. We used conditional deletion of CB2 receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB2 agonists. Anti-allodynic effects of structurally distinct CB2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB2f/f mice and in mice lacking CB2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1CRE/+; CB2f/f), but were absent in mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB2f/f and CX3CR1CRE/+; CB2f/f mice with established paclitaxel-induced neuropathy but was absent in male (or female) AdvillinCRE/+; CB2f/f mice. Co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB2f/f mice, but not AdvillinCRE/+; CB2f/f mice of either sex. LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB2f/f or CX3CR1CRE/+; CB2f/f mice of either sex. Our findings have potential clinical implications.

Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.

A case of cardiac undifferentiated pleomorphic sarcoma in late pregnancy: A case report.

Cardiac tumors are uncommon and most of them are benign. Although cases of malignant cardiac tumors are rare, it is still necessary to improve awareness in both clinical and pathological diagnosis. Since cardiac tumors often have a high degree of malignancy, it is vital to determine what form of intervention can increase recurrence-free survival and overall survival. In this paper, we report on a 42-year-old woman in the third trimester of pregnancy who had a cardiac undifferentiated pleomorphic sarcoma. According to her medical history, the patient had never had a cardiac tumor or any other disease. She was treated surgically and a left atrial mass was removed immediately after cesarean section. No other treatments were applied after the surgery, and, unfortunately, the tumor reoccurred 6 months later. We reviewed some literature and found one case in which the patient was treated using radiotherapy and survived for another 2 years after the third tumor recurrence. This suggests that neoadjuvant therapy effectively improves the survival rates of such patients.

Bayesian variable selection in joint modeling of longitudinal data and interval-censored failure time data.

Joint modeling of longitudinal data and survival data has gained great attention in the last two decades. However, most of the existing studies have focused on right-censored survival data. In this article, we study joint analysis of longitudinal data and interval-censored survival data and conduct Bayesian variable selection in this framework. A new joint model is proposed with a shared frailty to characterize the dependence between the two types of responses, where the longitudinal response is modeled with a semiparametric linear mixed-effects submodel and the survival time is modeled by a semiparametric normal fraility probit sub-model. Several Bayesian variable selection approaches are developed by adopting Bayesian Lasso, adaptive Lasso, and spike-and-slab priors in order to simultaneously select significant covariates and estimate their effects on the two types of responses. Efficient Gibbs samplers are proposed with all unknown parameters and latent variables being sampled directly from well recognized full conditional distributions. Our simulation study shows that these methods perform well in both variable selection and parameter estimation. A real-life data application to joint analysis of blood cholesterol level and hypertension is provided as an illustration.

Exosome is a Fancy Mobile Sower of Ferroptosis.

Exosomes, nano-sized small extracellular vesicles, have been shown to serve as mediators between intercellular communications by transferring bioactive molecules, such as non-coding RNA, proteins, and lipids from secretory to recipient cells, modulating a variety of physiological and pathophysiological processes. Recent studies have gradually demonstrated that altered exosome charges may represent a key mechanism driving the pathological process of ferroptosis. This review summarizes the potential mechanisms and signal pathways relevant to ferroptosis and then discusses the roles of exosome in ferroptosis. As well as transporting iron, exosomes may also indirectly convey factors related to ferroptosis. Furthermore, ferroptosis may be transmitted to adjacent cells through exosomes, resulting in cascading effects. It is expected that further research on exosomes will be conducted to explore their potential in ferroptosis and will lead to the creation of new therapeutic avenues for clinical diseases.

Impact of low-dose aspirin exposure on obstetrical outcomes: a meta-analysis.

OBJECTIVE: To assess the impact of low-dose aspirin (LDA) on obstetrical outcomes through a meta-analysis of placebo-controlled randomized controlled trials (RCTs). METHODS: A systematic search of the PubMed, Cochrane Library, Web of Science and Embase databases from inception to January 2024 was conducted to identify studies exploring the role of aspirin on pregnancy, reporting obstetrical-related outcomes, including preterm birth (PTB, gestational age <37 weeks), small for gestational age (SGA), low birth weight (LBW, birthweight < 2500g), perinatal death (PND), admission to the neonatal intensive care unit (NICU), 5-min Apgar score < 7 and placental abruption. Relative risks (RRs) were estimated for the combined outcomes. Subgroup analyses were performed by risk for preeclampsia (PE), LDA dosage (<100 mg vs. ≥100 mg) and timing of onset (≤20 weeks vs. >20 weeks). RESULTS: Forty-seven studies involving 59,124 participants were included. Compared with placebo, LDA had a more significant effect on low-risk events such as SGA, PTB and LBW. Specifically, LDA significantly reduced the risk of SGA (RR = 0.91, 95% CI: 0.87-0.95), PTB (RR = 0.93, 95% CI: 0.89-0.97) and LBW (RR = 0.94, 95% CI: 0.89-0.99). For high-risk events, LDA significantly lowered the risk of NICU admission (RR = 0.93, 95% CI: 0.87-0.99). On the other hand, LDA can significantly increase the risk of placental abruption (RR = 1.72, 95% CI: 1.23-2.43). Subgroup analyses showed that LDA significantly reduced the risk of SGA (RR = 0.86, 95% CI: 0.77-0.97), PTB (RR = 0.93, 95% CI: 0.88-0.98) and PND (RR = 0.65, 95% CI: 0.48-0.88) in pregnant women at high risk of PE, whereas in healthy pregnant women LDA did not significantly improve obstetrical outcomes, but instead significantly increased the risk of placental abruption (RR = 5.56, 95% CI: 1.92-16.11). In pregnant women at high risk of PE, LDA administered at doses ≥100 mg significantly reduced the risk of SGA (RR = 0.77, 95% CI: 0.66-0.91) and PTB (RR = 0.56, 95% CI: 0.32-0.97), but did not have a statistically significant effect on reducing the risk of NICU, PND and LBW. LDA started at ≤20 weeks significantly reduced the risk of SGA (RR = 0.76, 95% CI: 0.65-0.89) and PTB (RR = 0.56, 95% CI: 0.32-0.97). CONCLUSIONS: To sum up, LDA significantly improved neonatal outcomes in pregnant women at high risk of PE without elevating the risk of placental abruption. These findings support LDA's clinical application in pregnant women, although further research is needed to refine dosage and timing recommendations.

Thermally Robust Solvent-Free Liquid Polyplexes for Heat-Shock Protection and Long-Term Room Temperature Storage of Therapeutic Nucleic Acids.

Nucleic acid therapeutics have attracted recent attention as promising preventative solutions for a broad range of diseases. Nonviral delivery vectors, such as cationic polymers, improve the cellular uptake of nucleic acids without suffering the drawbacks of viral delivery vectors. However, these delivery systems are faced with a major challenge for worldwide deployment, as their poor thermal stability elicits the need for cold chain transportation. Here, we demonstrate a biomaterial strategy to drastically improve the thermal stability of DNA polyplexes. Importantly, we demonstrate long-term room temperature storage with a transfection efficiency maintained for at least 9 months. Additionally, extreme heat shock studies show retained luciferase expression after heat treatment at 70 °C. We therefore provide a proof of concept for a platform biotechnology that could provide long-term room temperature storage for temperature-sensitive nucleic acid therapeutics, eliminating the need for the cold chain, which in turn would reduce the cost of distributing life-saving therapeutics worldwide.

Combined hysteroscopic Bigatti shaver (IBS) and resectoscope removal of a heterotopic cesarean scar pregnancy in the first trimester.

OBJECTIVE: To report a case of heterotopic cesarean scar pregnancy reduction using a combined hysteroscopic integrated Bigatti shaver (IBS) and resectoscope with the preservation of a normal gestational sac in the uterine cavity under simultaneous transabdominal ultrasound guidance. DESIGN: Video article. SETTING: University-affiliated hospital. PATIENT: A 30-year-old woman, G5P2A2L2, with two previous cesarean deliveries and a history of fertility problems, was admitted with a heterotopic cesarean scar pregnancy at 7+2 gestational weeks. Ultrasound examination showed a dichorionic diamniotic pregnancy. The first gestational sac (1.7 × 1.7 × 0.6 cm) was located in the previous hysterotomy scars, with a thin layer of myometrium measuring 0.2 cm in thickness and a rich blood supply. The second chorionic sac (2.8 × 2.4 × 1.8 cm) was observed at the uterine fundus. Normal cardiac activity and yolk sacs were observed in both gestational sacs. The couple strongly desired to preserve the intrauterine pregnancy. INTERVENTION(S): After Institutional Review Board approval was obtained, a hysteroscopic IBS combined with a bipolar resectoscope was used to remove the heterotopic cesarean scar pregnancy while preserving the intrauterine gestational sac under simultaneous transabdominal ultrasound guidance. MAIN OUTCOME MEASURE(S): The heterotopic cesarean scar pregnancy was completely resected using hysteroscopy, and the gestational sac in the uterine cavity was successfully preserved. RESULT(S): Trophoblastic tissue was confirmed using histopathological examination. The patient had an unremarkable postoperative recovery. Subsequent serial ultrasonography confirmed a single ongoing pregnancy with normal growth parameters and a normal placental site. CONCLUSION(S): The inability of an IBS to perform coagulation can be offset by its combination with the bipolar resectoscope. Hysteroscopic IBS combined with resectoscope to remove a heterotopic cesarean scar pregnancy offers a short operation time and minimum blood loss. It could be an optimized approach for the management of heterotopic cesarean scar pregnancy in the first trimester when an intrauterine pregnancy needs to be preserved.

The FBXW7-binding sites on FAM83D are potential targets for cancer therapy.

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.

A novel approach to evaluation of tumor response for advanced pulmonary adenocarcinoma using the intertumoral heterogeneity response score.

Treatment response and prognosis estimation in advanced pulmonary adenocarcinoma are challenged by the significant heterogeneity of the disease. The current Response Evaluation Criteria in Solid Tumors (RECIST) criteria, despite providing a basis for solid tumor response evaluation, do not fully encompass this heterogeneity. To better represent these nuances, we introduce the intertumoral heterogeneity response score (THRscore), a measure built upon and expanding the RECIST criteria. This retrospective study included patients with 3-10 measurable advanced lung adenocarcinoma lesions who underwent first-line chemotherapy or targeted therapy. The THRscore, derived from the coefficient of variation in size for each measurable tumor before and 4-6 weeks posttreatment, unveiled a correlation with patient outcomes. Specifically, a high THRscore was associated with shorter progression-free survival, lower tumor response rate, and a higher tumor mutation burden. These associations were further validated in an external cohort, confirming THRscore's effectiveness in stratifying patients based on progression risk and treatment response, and enhancing the utility of RECIST in capturing complex tumor behaviors in lung adenocarcinoma. These findings affirm the promise of THRscore as an enhanced tool for tumor response assessment in advanced lung adenocarcinoma, extending the RECIST criteria's utility.

Cannabinoid CB 2 receptors in primary sensory neurons are implicated in CB 2 agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance.

Cannabinoid CB 2 agonists show therapeutic efficacy without the unwanted side effects commonly associated with direct activation of CB 1 receptors. The G protein-biased CB 2 receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks the development of morphine tolerance in this model. However, the specific cell types involved in this phenomenon have never been investigated and whether this therapeutic profile is observed in female mice remains poorly understood. We used conditional deletion of CB 2 receptors from specific cell populations to determine the population(s) mediating the anti-allodynic and morphine-sparing effects of CB 2 agonists. Anti-allodynic effects of structurally distinct CB 2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB 2 f/f mice of either sex. The anti-allodynic effect of the CB 2 agonists were absent in conditional knockout (KO) mice lacking CB 2 receptors in peripheral sensory neurons (Advillin CRE/+ ; CB 2 f/f ) but preserved in mice lacking CB 2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1 CRE/+ ; CB 2 f/f ). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male mice but absent in female mice of any genotype. In mice with established paclitaxel-induced neuropathy, prior LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the subsequent development of morphine tolerance in male CB 2 f/f mice but was absent in male (or female) Advillin CRE/+ ; CB 2 f/f mice. LY2828360-induced sparing of morphine tolerance was preserved in male CX3CR1 CRE/+ ; CB 2 f/f mice, but this effect was not observed in female CX3CR1 CRE/+ ; CB 2 f/f mice. Similarly, co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed tolerance to the anti-allodynic efficacy of morphine in paclitaxel-treated male CB 2 f/f mice, but this effect was absent in female CB 2 f/f mice and Advillin CRE/+ ; CB 2 f/f mice of either sex. Additionally, LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical and cold allodynia in either CB 2 f/f or CX3CR1 CRE/+ ; CB 2 f/f mice of either sex. Our studies reveal that CB 2 receptors in primary sensory neurons are required for the anti-allodynic effects of CB 2 agonists in a mouse model of paclitaxel-induced neuropathic nociception. We also find that CB 2 agonists acting on primary sensory neurons produce a sexually-dimorphic sparing of morphine tolerance in males, but not female, paclitaxel-treated mice.