Safety of pembrolizumab as adjuvant therapy in a pooled analysis of phase 3 clinical trials of melanoma, non-small cell lung cancer, and renal cell carcinoma.

BACKGROUND: The safety profile of adjuvant pembrolizumab was evaluated in a pooled analysis of 4 phase 3 clinical trials. METHODS: Patients had completely resected stage IIIA, IIIB, or IIIC melanoma per American Joint Committee on Cancer, 7th edition, criteria (AJCC-7; KEYNOTE-054); stage IIB or IIC melanoma per AJCC-8 (KEYNOTE-716); stage IB, II, or IIIA non-small cell lung cancer per AJCC-7 (PEARLS/KEYNOTE-091); or postnephrectomy/metastasectomy clear cell renal cell carcinoma at increased risk of recurrence (KEYNOTE-564). Patients received adjuvant pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for approximately 1 year. Adverse events (AEs) were summarized for patients who received ≥ 1 dose of treatment. RESULTS: Data were pooled from 4125 patients treated with pembrolizumab (n = 2060) or placebo (n = 2065). Median (range) duration of treatment was 11.1 months (0.0-18.9) with pembrolizumab and 11.2 months (0.0-18.1) with placebo. Treatment-related AEs occurred in 78.6 % (1620/2060) of patients in the pembrolizumab group (grade 3-5, 16.3 % [336/2060]) and 58.7 % (1212/2065) in the placebo group (grade 3-5, 3.5 % [72/2065]). Immune-mediated AEs (e.g. adrenal insufficiency, hypophysitis, and thyroiditis) occurred in 36.2 % (746/2060) of patients in the pembrolizumab group (grade 3-5, 8.6 % [177/2060]) and 8.4 % (174/2065) in the placebo group (grade 3-5, 1.1 % [23/2065]). Of patients with ≥ 1 immune-mediated AE or infusion reaction, systemic corticosteroids were required for 35.2 % (268/761) and 20.2 % (39/193) of patients in the pembrolizumab and placebo groups, respectively. CONCLUSIONS: Adjuvant pembrolizumab demonstrated a manageable safety profile that was comparable to prior reports in advanced disease.

Hepatic-associated vascular morphological assessment to predict overt hepatic encephalopathy before TIPS: a multicenter study.

BACKGROUND: To provide patients the chance of accepting curative transjugular intrahepatic portosystemic shunt (TIPS) rather than palliative treatments for portal hypertension-related variceal bleeding and ascites, we aimed to assess hepatic-associated vascular morphological change to improve the predictive accuracy of overt hepatic encephalopathy (HE) risks. METHODS: In this multicenter study, 621 patients undergoing TIPS were subdivided into training (413 cases from 3 hospitals) and external validation datasets (208 cases from another 3 hospitals). In addition to traditional clinical factors, we assessed hepatic-associated vascular morphological changes using maximum diameter (including absolute and ratio values). Three predictive models (clinical, hepatic-associated vascular, and combined) were constructed using logistic regression. Their discrimination and calibration were compared to test the necessity of hepatic-associated vascular assessment and identify the optimal model. Furthermore, to verify the improved performance of ModelC-V, we compared it with four previous models, both in discrimination and calibration. RESULTS: The combined model outperformed the clinical and hepatic-associated vascular models (training: 0.814, 0.754, 0.727; validation: 0.781, 0.679, 0.776; p < 0.050) and had the best calibration. Compared to previous models, ModelC-V showed superior performance in discrimination. The high-, middle-, and low-risk populations displayed significantly different overt HE incidence (p < 0.001). Despite the limited ability of pre-TIPS ammonia to predict overt HE risks, the combined model displayed a satisfactory ability to predict overt HE risks, both in the low- and high-ammonia subgroups. CONCLUSION: Hepatic-associated vascular assessment improved the predictive accuracy of overt HE, ensuring curative chances by TIPS for suitable patients and providing insights for cirrhosis-related studies.

Real-time detection of gastrointestinal leaks via bismuth chelate-enhanced X-ray gastroenterography.

Anastomotic leaks are among the most dreaded complications following gastrointestinal (GI) surgery, and contrast-enhanced X-ray gastroenterography is considered the preferred initial diagnostic method for GI leaks. However, from fundamental research to clinical practice, the only oral iodinated contrast agents currently available for GI leaks detection are facing several challenges, including low sensitivity, iodine allergy, and contraindications in patients with thyroid diseases. Herein, we propose a cinematic contrast-enhanced X-ray gastroenterography for the real-time detection of GI leaks with an iodine-free bismuth chelate (Bi-DTPA) for the first time. The Bi-DTPA, synthesized through a straightforward one-pot method, offers distinct advantages such as no need for purification, a nearly 100 % yield, large-scale production capability, and good biocompatibility. The remarkable X-ray attenuation properties of Bi-DTPA enable real-time dynamic visualization of whole GI tract under both X-ray gastroenterography and computed tomography (CT) imaging. More importantly, the leaky site and severity can be both clearly displayed during Bi-DTPA-enhanced gastroenterography in a rat model with esophageal leakage. The proposed movie-like Bi-DTPA-enhanced X-ray imaging approach presents a promising alternative to traditional GI radiography based on iodinated molecules. It demonstrates significant potential in addressing concerns related to iodine-associated adverse effects and offers an alternative method for visually detecting gastrointestinal leaks.

Cervical cancer-specific long non-coding RNA landscape reveals the favorable prognosis predictive performance of an ion-channel-related signature model.

BACKGROUND: Ion channels play an important role in tumorigenesis and progression of cervical cancer. Multiple long non-coding RNA genes are widely involved in ion channel-related signaling regulation. However, the association and potential clinical application of lncRNAs in the prognosis of cervical cancer are still poorly explored. METHODS: Thirteen patients with cervical cancer were enrolled in current study. Whole transcriptome (involving both mRNAs and lncRNAs) sequencing was performed on fresh tumor and adjacent normal tissues that were surgically resected from patients. A comprehensive cervical cancer-specific lncRNA landscape was obtained by our custom pipeline. Then, a prognostic scoring model of ion-channel-related lncRNAs was established by regression algorithms. The performance of the predictive model as well as its association with the clinical characteristics and tumor microenvironment (TME) status were further evaluated. RESULTS: To comprehensively identify cervical cancer-specific lncRNAs, we sequenced 26 samples of cervical cancer patients and integrated the transcriptomic results. We built a custom analysis pipeline to improve the accuracy of lncRNA identification and functional annotation and obtained 18,482 novel lncRNAs in cervical cancer. Then, 159 ion channel- and tumorigenesis-related (ICTR-) lncRNAs were identified. Based on nine ICTR-lncRNAs, we also established a prognostic scoring model and validated its accuracy and robustness in assessing the prognosis of patients with cervical cancer. Besides, the TME was characterized, and we found that B cells, activated CD8+ T, and tertiary lymphoid structures were significantly associated with ICTR-lncRNAs signature scores. CONCLUSION: We provided a thorough landscape of cervical cancer-specific lncRNAs. Through integrative analyses, we identified ion-channel-related lncRNAs and established a predictive model for assessing the prognosis of patients with cervical cancer. Meanwhile, we characterized its association with TME status. This study improved our knowledge of the prominent roles of lncRNAs in regulating ion channel in cervical cancer.

Elective Irradiation of Retropharyngeal Lymph Nodes as an Indication for Adjuvant Radiation Therapy After Transoral Surgery for Tonsil Cancer.

Treatment of squamous cell carcinoma of the tonsil involves primary radiation therapy (RT) or surgical resection. Historically, if RT was the primary or adjuvant treatment modality, most of the bilateral retropharyngeal lymph nodes (RPLNs) were treated electively with a therapeutic dose for subclinical disease, regardless of whether radiographically pathologic lymph nodes were seen on initial diagnostic imaging. De-escalation strategies include the incorporation of transoral surgery with the goal to either eliminate or reduce the dose of adjuvant RT or chemotherapy. Transoral surgery does not include elective removal of the RPLNs, and no guideline or outcome paper recommends adjuvant RT specifically to electively treat RPLNs. In this Topic Discussion, we discuss pertinent literature and suggest management decisions. The management decisions discussed in this Topic Discussion pertain to only tonsillar primaries and not those of the soft palate or base of the tongue.

Predictive Modeling for Functional Outcomes After All-Inside Arthroscopic Anterior Talofibular Ligament Repair of Chronic Ankle Instability.

BACKGROUND: Arthroscopic anterior talofibular ligament repair (AATFLR) is a surgical strategy to treat chronic ankle instability (CAI) patients. This study identified risk factors that influenced the functional outcomes of AATFLR for CAI and developed prognostic nomogram for predicting functional outcomes in future AATFLR cases. METHODS: Patients undergoing AATFLR from January 2016 to June 2022 with at least 10 months of follow-up were included in the study. The Karlsson Ankle Functional Score (KAFS) was evaluated preoperatively and at last follow-up visit. A total of 15 potential predictors including age, sex, body mass index, side affected, time from injury to surgery, sports-related injury, osteophyte, loose bodies, distal tibiofibular syndesmosis, ATFL avulsion fracture, Outerbridge classification of osteochondral lesions, postoperative immobilization method, ambulation time, walking time, and follow-up time, were recorded. We first used univariate binary logistic regression analysis to select the potential significant prognostic features, which were then subjected to the least absolute shrinkage and selection operator (LASSO) regression algorithm for final feature selection. A nomogram based on the regression model was developed to estimate the functional outcomes of patients. Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. RESULTS: Overall, 200 ankles fit inclusion criteria. Of these 200, a total of 185 (92.5%) ankles were eligible and divided into development (n = 121) and validation (n = 64) cohorts. Four predictors were ultimately included in the prognostic nomogram model: age, sex, sports-related injury, and postoperative immobilization method. CONCLUSION: We found in our cohort that the significant predictors of poorer functional outcomes of AATFLR were postoperative immobilization with lower-leg cast, female sex, non-sports-related ankle sprain, and increasing age. Prognostic nomograms were created. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Candidate membrane protein gene families related to chemoreception in a wood-boring beetle, Pharsalia antennata Gahan (Coleoptera: Cerambycidae).

The longhorned beetles are key players for the maintenance of biodiversity in the terrestrial ecosystem. As xylophagous cerambycid insects in Coleoptera, the beetles have evolved specialized olfactory and gustatory systems to recognize chemical cues in the surrounding habitats. Despite over 36,000 described species in the Cerambycidae family including a wood-boring pest Pharsalia antennata, only a limited number of them (<1 %) have been characterized regarding their chemical ecology at the molecular level. Here, we surveyed four membrane protein gene families in P. antennata related to chemoreception through transcriptomics, phylogenetics and expression profiling analyses. In total, 144 genes encoding 72 odorant receptors (ORs), 33 gustatory receptors (GRs), 23 ionotropic receptors (IRs), four sensory neuron membrane proteins (SNMPs) and 12 ionotropic glutamate receptors (iGluRs) were harvested from the transcriptome of multiple tissues including antennae and legs of both sexes. The lineage-specific expansion of PantORs possibly implied a diverse range of host plants in this beetle, supporting this correlation between the host range and olfactory receptor repertoire sizes across cerambycid species. Further phylogenetic analysis revealed that Group 2 was contributed mainly to the large OR gene repertoire in P. antennata, representing 18 genes in Group 2A and eight in Group 2B. On the other hand, some key chemosensory genes were identified by applying a phylogenetics approach, such as PantOR21 close to the 2-phenylethanol receptor in Megacyllene caryae, three carbon dioxide GRs and seven Antennal IRs (A-IRs) clades. We also determined sex- and tissue-specific expression profiles of 69 chemosensory genes, revealing the high expression of most PantORs in antennae. Noticeably, 10 sex-biased genes (six PantORs, three PantIRs and PantSNMP1a) were presented in antennae, five sex-biased PantGRs in legs and 39 sex-biased genes (15 PantORs, 13 PantGRs, eight PantIRs and three PantSNMPs) in abdomens. These findings have greatly enhanced our knowledge about the chemical ecology of P. antennata and identify candidate molecular targets for mediating smell and taste of this beetle.

IGF2BP2-Shox2 axis regulates hippocampal-neuronal senescence to alleviate microgravity-induced recognition disturbance.

During space travel, microgravity leads to disturbances in cognitive function, while the underlying mechanism is still unclear. Simulated microgravity mice showed neuronal age-like changes in the hippocampus of our study. In the context of microgravity, we discovered m6A modification reshapes in the hippocampal region. When paired with RNA-seq and MeRIP-seq, Shox2 was found to be a powerful regulator in hippocampal neuron that respondes to microgravity. Decreased expression of senescence-associated secretory phenotype factors and improved genes related to synapses led to the restoration of memory function in the hippocampus upon increased expression of Shox2. Moreover, we discovered that IGF2BP2 was required for the m6A modification of the Shox2, and overexpressed IGF2BP2 in the hippocampus protected against both neuronal senescence and learning and memory decline caused by loss of gravity. Accordingly, our research identified the hippocampal IGF2BP2-Shox2 axis as a possible therapeutic approach to maintaining cognitive function during space travel.

Mitophagy Regulates the Circadian Rhythms by Degrading NR1D1 in Simulated Microgravity and Isolation Environments.

Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, but the underlying molecular mechanisms remain unclear. Here, we developed a rat model that simulated microgravity and isolation environments through tail suspension and isolation (TSI). We found that the TSI environment imposed circadian disruptions to the core body temperature, heart rate, and locomotor-activity rhythms of rats, especially in the amplitude of these rhythms. In TSI model rats' SCNs, the core circadian gene NR1D1 showed higher protein but not mRNA levels along with decreased BMAL1 levels, which indicated that NR1D1 could be regulated through post-translational regulation. The autophagosome marker LC3 could directly bind to NR1D1 via the LC3-interacting region (LIR) motifs and induce the degradation of NR1D1 in a mitophagy-dependent manner. Defects in mitophagy led to the reversal of NR1D1 degradation, thereby suppressing the expression of BMAL1. Mitophagy deficiency and subsequent mitochondrial dysfunction were observed in the SCN of TSI models. Urolithin A (UA), a mitophagy activator, demonstrated an ability to enhance the amplitude of core body temperature, heart rate, and locomotor-activity rhythms by prompting mitophagy induction to degrade NR1D1. Cumulatively, our results demonstrate that mitophagy exerts circadian control by regulating NR1D1 degradation, revealing mitophagy as a potential target for long-term spaceflight as well as diseases with SCN circadian disruption.

A Zero-Gap Gas Phase Photoelectrolyzer for CO2 Reduction with Porous Carbon Supported Photocathodes.

A modified Metal-Organic Framework UiO-66-NH2-based photocathode in a zero-gap gas phase photoelectrolyzer was applied for CO2 reduction. Four types of porous carbon fiber layers with different wettability were employed to tailor the local environment of the cathodic surface reactions, optimizing activity and selectivity towards formate, methanol, and ethanol. Results are explained by mass transport through the different type and arrangement of carbon fiber support layers in the photocathodes and the resulting local environment at the UiO-66-NH2 catalyst. The highest energy-to-fuel conversion efficiency of 1.06 % towards hydrocarbons was achieved with the most hydrophobic carbon fiber (H23C2). The results are a step further in understanding how the design and composition of the photoelectrodes in photoelectrochemical electrolyzers can impact the CO2 reduction efficiency and selectivity.

Commercializable Naphthalene Diimide Anolytes for Neutral Aqueous Organic Redox Flow Batteries.

Neutral aqueous organic redox flow batteries (AORFBs) hold the potential to facilitate the transition of renewable energy sources from auxiliary to primary energy, the commercial production of anolyte materials still suffers from insufficient performance of high-concentration and the high cost of the preparation problem. To overcome these challenges, this study provides a hydrothermal synthesis methodology and introduces the charged functional groups into hydrophobic naphthalene diimide cores, and prepares a series of high-performance naphthalene diimide anolytes. Under the synergistic effect of π-π stacking and H-bonding networks, the naphthalene diimide exhibits excellent structural stability and the highest water solubility (1.85 M for dex-NDI) reported to date. By employing the hydrothermal method, low-cost naphthalene diimides are successfully synthesized on a hundred-gram scale of $0.16 g-1 ($2.43 Ah-1), which is also the lowest price reported to date. The constructed full battery achieves a high electron concentration of 2.4 M, a high capacity of 54.4 Ah L-1, and a power density of 318 mW cm-2 with no significant capacity decay observed during long-duration cycling. These findings provide crucial support for the commercialization of AORFBs and pave the way for revolutionary developments in neutral AORFBs.

Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups). RESULTS: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], P<0.0001) with a consistent effect across all 3 patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], P<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], P=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], P=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pinteraction=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.

Body Compositions Correlate With Overt Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt: A Multicentre Cohort Study.

BACKGROUND: The relationship between body composition and the risk of overt hepatic encephalopathy (OHE) following transjugular intrahepatic portosystemic shunt (TIPS) needs to be investigated. METHODS: Overall, 571 patients from 5 medical centers were included. To assess body compositions, we evaluated skeletal muscle indices, adipose tissue indices, sarcopenia, and myosteatosis at the third lumbar vertebral level. Univariate and Multivariate logistic regression analyses were performed to identify independent risk factors for post-TIPS OHE. An integrated score was then constructed using stepwise multiple regression analyses, with a cut-off value selected using the best Youden index. Finally, the Akaike information criterion (AIC) was performed to compare the integrated score and independent risk factors on their ability in predicting post-TIPS OHE. RESULTS: Sarcopenia and all skeletal muscle indices had limited associations with post-TIPS OHE. The index of the subcutaneous adipose tissue (SATI) (P=0.005; OR: 1.034, 95% CI: 1.010-1.058) and myosteatosis (297 cases, 52.01%, 125 with OHE, 42.09%; P=0.003; OR: 1.973; 95% CI: 1.262-3.084) were both ascertained as independent risk factors for post-TIPS OHE. The integrated score (ScoreALL=1.5760 + 0.0107 * SATI + 0.8579 * myosteatosis) was established with a cutoff value of -0.935. The akaike information criterion (AIC) of ScoreALL, SATI, and myosteatosis was 655.28, 691.18, and 686.60, respectively. CONCLUSIONS: SATI and myosteatosis are independent risk factors for post-TIPS OHE. However, the integrated score was more significantly associated with post-TIPS OHE than other skeletal muscle and adipose tissue factors.

Investigation of Tribological Behavior and Lubrication Mechanisms of Zinc Oxide under Poly α-olefin Lubrication Enhanced by the Electric Field.

The electric field induces complex effects on the tribological properties of zinc oxide (ZnO) under lubricated conditions, particularly at the nanoscale, where the friction process and mechanism remain unclear. In this paper, the tribological behaviors of ZnO under the lubrication of poly α-olefins (PAO) were investigated by molecular dynamics (MD) simulations with reactive force field (ReaxFF). The results reveal a significant enhancement in the tribological performances of ZnO with the application of the electric field, resulting in a 58.6% reduction in the coefficient of friction (COF) from 0.193 at 0 V/Å to 0.080 at 0.1 V/Å. This improvement can be attributed to the weakening of interfacial interaction, evidenced by a reduction in the number of C-O covalent bonds under the influence of the electric field, along with the formation of an adsorption film due to applied load and shear effects. Notably, the effect of the electric field and applied load extends the impact of interface slip on the tribological performance of ZnO. Overall, this study provides a comprehensive understanding of the impact of the electric field on reducing the friction of ZnO-based structured models, shedding light on explaining their tribological properties and lubrication mechanisms.

Effects of dietary Artemisia annua supplementation on growth performance, antioxidant capacity, immune function, and gut microbiota of geese.

This experiment aimed to study the effect of 1% Artemisia annua added to the diet on growth performance, antioxidant capacity, immunity and intestinal morphology, and gut microbiota of geese. Seventy-two 35-day-old male geese (Zi goose) with similar body weight were selected and randomly divided into 2 groups. Each treatment group of 36 geese was divided into 6 subgroups, each having 6 male geese. The experiment lasted for 21 d. Control group (CON) was fed a basal diet and the experimental group (AAL) was fed a basal diet + 1% Artemisia annua. BW, ADG, and ADFI of the AAL group increased (p < 0.05) and the FCR decreased (p < 0.05) compared with the CON group. The addition of Artemisia annua to the diet increased catalase (CAT), glutathione peroxidase (GSH-px), and superoxide dismutase (SOD) enzyme activities, increased total antioxidant capacity (T-AOC), and decreased malondialdehyde (MDA) content in serum and jejunum of geese (p < 0.05). Meanwhile, serum IgA, IgG, IgM, and lysozyme (LZM), increased at different time points in the AAL group compared to the CON group (p < 0.05), and decrease in the content of interferon-γ (IFN-γ) , IL-6 (p < 0.05), but no effect on complement C3 and C4. Morphological observation of the small intestine showed that the jejunal crypt depth was decreased in the AAL group (p < 0.05) while elevating the jejunal villus height/crypt depth (p < 0.05). 16S rRNA sequencing results showed the Artemisia annua increased the diversity of cecum microbiota, increasing the relative abundance of Bacteroides, Fecalibacterium, and Paraprevotella. In conclusion, the addition of 1% Artemisia annua to the diet could improve the growth performance, antioxidant and immune ability of geese, as well as improve the development of the jejunum intestinal tract of geese, and change the structure of the cecum microbiota, which had a positive effect on the growth and development of geese. Artemisia annua can be further developed as a feed additive.

Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial.

BACKGROUND: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. METHODS: Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm2 (median) vs ≥5 per mm2), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). RESULTS: Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm2 and 0.57 (0.40 to 0.80) for ≥5 per mm2; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. CONCLUSIONS: In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03553836.

Short time effects of two radiofrequency ablation methods on hypertrophic obstructive cardiomyopathy.

BACKGROUND: Radiofrequency ablation has been applied for the treatment of hypertrophic obstructive cardiomyopathy (HOCM). The two known procedures are percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) and endocardial radiofrequency septal ablation (ERSA). METHODS: This study presents a retrospective analysis of the PIMSRA and ERSA procedures in patients with drug-refractory HOCM. A total of 28 patients participated in the study, with 12 receiving PIMSRA and 16 receiving ERSA. The objective of our study was to compare the short-term effects of these two radiofrequency ablation procedures. RESULTS: At the 30-day follow-up, the PIMSRA group demonstrated a greater reduction in left ventricular outflow tract peak gradient at rest compared to the ERSA group (22.25 [16.72] mmHg versus 47.75 [21.94] mmHg) (p < .01). The values for the PIMSRA group decreased from 99.33 (32.00) mmHg to 22.25 (16.72) mmHg (p < .01), while the ERSA group decreased from 97.75 (30.24) mmHg to 47.75 (21.94) mmHg (p < .01). Only the PIMSRA group exhibited a decrease in mitral regurgitation (MR). The area of MR decreased from 10.13 (4.12) mm2 to 3.65 (2.80) mm2 in the PIMSRA group (p < .01). Additionally, the PIMSRA group experienced reductions in left atrial diameter (LAD) and left ventricular ejection fraction (LVEF)%. The values for LAD changed from 43.58 (7.53) mm to 37.08 (6.92) mm (p = .03), and the values for LVEF% decreased from 65.75 (6.12) pg/mL to 60.83 (4.06) pg/mL (p = .03). CONCLUSION: In terms of the two types of radiofrequency ablation methods used in HOCM, it has been observed that PIMSRA demonstrates a more favorable early treatment effect compared to ERSA.

The role of immunotherapy sensitizers and novel immunotherapy modalities in the treatment of cancer.

The importance of the immune system in the response against cancer has always been a subject of intense investigation. The advent of immune checkpoint inhibitors has transformed the landscape of oncologic treatments, while expanding the understanding of this disease's pathophysiology. Consequently, many therapies are being investigated, with interventions directed at different steps and pathways of the immune response. Relevantly, immunotherapy sensitizers have arisen as approaches focused on the synergistic effects of immunotherapy combination, or the combination of immunotherapy and other treatment modalities, such as chemotherapy or radiation therapy. Concomitantly, novel immunotherapy modalities are also in development. Approaches focusing from the tumor intrinsic pathways to the tumor microenvironment and ex-vivo interventions, such as CAR-T cell therapies and tumor-infiltrating lymphocytes are important examples. Although many of those interventions were initially envisioned as standalone options, their combination has demonstrated promising results in early-phase in vitro studies and clinical trials. The possibility of coupling different immunotherapy modalities, as well as with other techniques, further strengthen the concept of sensitizers, allowing for deeper and more robust responses in cancer treatment. This review aims to present an overview of the concepts of these sensitizing mechanisms that are the basis for the synergistic effects of immunotherapy combination, or the combination of immunotherapy and a multitude of therapeutic strategies. Novel immunotherapy modalities are also presented, focusing on the potential of combining them with sensitizer interventions. Understanding the complexity underlying these principles may be the key for future breakthroughs and improved patient outcomes.

Characterization of protective immune responses against Neisseria gonorrhoeae induced by intranasal immunization with adhesion and penetration protein.

Drug-resistant N. gonorrhoeae is an urgent threat to global public health, and vaccine development is the best long-term strategy for controlling gonorrhea. We have previously shown that adhesion and penetration protein (App) play a role in the adhesion, invasion, and reproductive tract colonization of N. gonorrhoeae. Here, we describe the immune response induced by intranasal immunization with passenger and translocator fragments of App. The recombinant App passenger and translocator fragments induced high titers of IgG and IgA antibodies in serum and vaginal washes. Antibodies produced by App passenger and the combination of passenger and translocator mediated the killing of N. gonorrhoeae via serum bactericidal activity and opsonophagocytic activity, whereas antisera from translocator-immunized groups had lower bactericidal activity and opsonophagocytic activity. The antisera of the App passenger and translocator, alone and in combination, inhibited the adhesion of N. gonorrhoeae to cervical epithelial cells in a concentration-dependent manner. Nasal immunization with App passenger and translocator fragments alone or in combination induced high levels of IgG1, IgG2a, and IgG2b antibodies and stimulated mouse splenocytes to secrete cytokines IFN-γ and IL-17A, suggesting that Th1 and Th17 cellular immune responses were activated. In vivo experiments have shown that immune App passenger and transporter fragments can accelerate the clearance of N. gonorrhoeae in the vagina of mice. These data suggest that the App protein is a promising N. gonorrhoeae vaccine antigen.

Hemorheology and Inflammatory Marker Changes in Patients with Acute Ischemic Stroke after Intravenous Thrombolysis with Mechanical Thrombectomy.

Objective: To investigate hemorheology and inflammatory marker changes after treatment for acute ischemic stroke (AIS) using intravenous thrombolysis (IVT) with mechanical thrombectomy (MT). Methods: We retrospectively reviewed clinical records of patients with AIS (n=83) treated in The First Affiliated Hospital of Bengbu Medical College between January 2021 and December 2022 (n=83). The control group consisted of 38 patients who underwent IVT alone and the observation group consisted of 45 patients who underwent IVT with MT. We compared differences in mean variables related to hemorheology, inflammatory markers, and total efficacy between the two groups. Results: We found that hemorheology values (plasma viscosity [PV], whole blood viscosity [WBV], fibrinogen [FIB], and hematocrit [HCT]), and the levels of inflammatory markers (tumor necrosis factor ɑ [TNF-ɑ] and interleukin-6 [IL-6]) were higher in the control group than in the observation group after treatment (P<0.05). In addition, the total efficacy of the observation group (93.3%) was higher than that in the control group (76.3%; P=0.016). Conclusions: The clinical efficacy of combined IVT and MT in the treatment of AIS is superior to IVT alone, improving levels of hemorheology and inflammatory markers in patients with AIS.