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In a companion paper we examined whether combinations of K

The purpose of the study was to evaluate the stress on the implant and to assess the denture displacement for locator and bar and clip attachment types in implant-assisted obturators.A maxillary edentulous experimental model with a maxillectomy defect was made along with an opposing edentulous mandibular model with self-cure acrylic. Two endosseous implants were placed in the maxillary model. Corresponding obturator complete denture was fabricated for the maxillary model and a complete denture for the mandibular. The attachments were positioned on the implants in maxillary model, and their sleeve/clip was placed on intaglio surface of the dentures. The mounted articulator was placed on a loading apparatus, and force was incrementally applied to it. The strain and displacement for both the attachment types were measured and compared using Digital Image Correlation (DIC).Locator attachment showed the least stress and minimal displacement as compared to bar and clip attachment.The stresses around the implants and displacement of the obturator are affected by the attachment type used. It was found that bar and clip (splinted) showed the maximum stresses around the implant and maximum denture displacement. Locator attachment is the better choice over bar and clip because of its additional retentive features.The advantage of using DIC over the conventional strain gauge analysis is that a full-field data of displacement and strain can be obtained instead of getting a mean value on the small surface where the strain gauge is positioned.

Doxorubicin (DOX) is an effective anti-cancer agent for various malignancies. Nevertheless, it has a side effect of cardiotoxicity, referred to as doxorubicin-induced cardiomyopathy (DIC), that is associated with a poorer prognosis. This cardiotoxicity limits the clinical use of DOX as a therapeutic agent for malignancies. Recently, ferroptosis, a form of regulated cell death induced by the accumulation of lipid peroxides, has been recognized as a major pathophysiology of DIC. Ethoxyquin is a lipophilic antioxidant widely used for food preservation and thus may be a potential therapeutic drug for preventing DIC. However, the efficacy of ethoxyquin against ferroptosis and DIC remains to be fully elucidated. Here, we investigated the inhibitory action of ethoxyquin against GPx4-deficient ferroptosis and its therapeutic efficacy against DOX-induced cell death in cultured cardiomyocytes and cardiotoxicity in a murine model of DIC. In cultured cardiomyocytes, ethoxyquin treatment effectively prevented GPx4-deficient ferroptosis. Ethoxyquin also prevented DOX-induced cell death, accompanied by the suppression of malondialdehyde (MDA) and mitochondrial lipid peroxides, which were induced by DOX. Furthermore, ethoxyquin significantly prevented DOX-induced cell death without any suppression of caspase cleavages representing apoptosis. In DIC mice, ethoxyquin treatment ameliorated cardiac impairments, such as contractile dysfunction and myocardial atrophy, and lung congestion. Ethoxyquin also suppressed serum lactate dehydrogenase and creatine kinase activities, decreased the levels of lipid peroxides such as MDA and acrolein, inhibited cardiac fibrosis, and reduced TUNEL-positive cells in the hearts of DIC mice. Collectively, ethoxyquin is a competent antioxidant for preventing ferroptosis in DIC and can be its prospective therapeutic drug.

Doxorubicin is a widely used anticancer drug in clinical practice, and its myocardial toxicity is the main concern in oncotherapy. Statins are commonly used as hypolipidemic drugs. Recent studies have also focused on the effects of statins on autophagy. Autophagy is a process in which cells consume their own cytoplasm or organelles after stimulation and finally degrade the phagosome in the lysosome. Transcription factor EB (TFEB) is the main factor regulating lysosomal gene transcription and function. We found that atorvastatin (ATO) increased TFEB protein levels and the ratio of lysosomal-associated membrane protein 2/LC3B in the myocardial tissue of mice with doxorubicin-induced cardiomyopathy (DIC). Therefore, we speculated that ATO may improve cardiac function in mice with DIC by increasing the expression of TFEB to enhance lysosomal function and autophagy. This study explored the role of TFEB in DIC and the possible mechanism of ATO in improving DIC and used statins to prevent and treat DIC; various dilated cardiomyopathy and heart failure diseases provide more experimental evidence. All relevant data are within the article and its supporting information files.

Across the last several years, numerous surgical departments and societies have focused on addressing the lack of diversity, equity, and inclusion (DEI) in the field. Since the Association of Program Directors in Surgery (APDS) Diversity and Inclusion Taskforce was created in 2017 (and solidified as a formal committee in 2018, herein referred to as the APDS-DIC), it has sought to address gaps in diversity at various phases of training and development from medical student to surgical leader.In follow-up to a 2018 study that benchmarked leadership demographics of the APDS, this study analyzed how the APDS' efforts have aligned with recommended DEI strategies and whether this produced demographic changes in organizational leadership.Fifteen years (2008-2022) of publicly available APDS annual meeting program data and APDS membership lists were analyzed. Leadership positions in the organization were examined by officer, program/vice chair, executive committee, and board of directors. A 2-tailed T-test compared differences in the average proportion of leaders from specific demographic groups before and after the APDS-DIC inception (2008-2016 vs. 2017-2022).APDS has 724 unique faculty and 140 resident members. The majority of both groups identified as White (68% of faculty and 58% of residents). Over 15 years, there have been 307 available leadership positions held by 67 individuals. All presidents and president-elect positions have been held by White surgeons; nearly 80% have been men. The average proportion of female leaders and the average proportion of racial/ethnic minority leaders were both significantly higher after implementation of the APDS-DIC in 2017 (p=0.0009 for gender and p=0.036 for racial/ethnic minorities).The APDS' commitment to DEI efforts and establishment of the APDS-DIC in 2017 was associated with a significant increase in women and non-White minorities in organizational leadership positions. The specific role of the APDS-DIC in propelling surgeons from underrepresented groups into leadership and promoting key DEI efforts is broadly applicable to other surgical organizations.

This study investigated the impact of colitis induced by dextran sulphate sodium (DSS)-induced colitis (DIC) on histopathological and immunological outcomes in the periodontal tissues of Wistar rats.Inflammatory bowel diseases (IBD) and periodontitis have been reported to present a bidirectional relationship. However, the inflammatory pathway that connects both diseases needs further investigation.Twenty-five male Wistar rats were allocated in four groups: unilateral ligature-induced periodontitis for 14 days: LIP (n = 7); dextran sulphate sodium-induced colitis only: DIC (n = 6); DIC + LIP (n = 6) and controls (n = 6). Digital images were obtained from the histological sections. In order to assess the attachment loss (AL), the linear distance between the cementoenamel junction (CEJ) and the alveolar bone crest was measured on the mesial root using histological photomicrography's ImageJ software. Immunological analyses of gingival tissues and plasma were performed by Bio-Plex Th1/Th2 Assay.The DIC group showed inflammatory cells extending to the periodontal connective tissues, which contained significantly elevated expressions of IL-1α, IL-1β, IL-2, IL-6, IL-12, IL-13, GM-CSF, IFN-γ and TNF-α compared to controls. There was no significant difference in bone loss between controls and DIC. There were no significant histopathological differences between DIC + LIP and LIP. However, DIC + LIP presented a significantly lower IL-2 and IL-5 than the LIP group. There was no bone loss difference between LIP+DIC and LIP groups. DIC + LIP group presented significantly higher levels of GM-CSF in plasma.DSS-induced colitis was associated with an overexpression of Th1/Th2- related cytokines in the gingival tissue.

Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no “one-size-fits-all criteria.” Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC.

Doxorubicin (DOX) is a class of effective chemotherapeutic agents widely used in clinical practice. However, its use has been limited by cardiotoxicity. The mechanism of DOX-induced cardiotoxicity (DIC) is complex, involving oxidative stress, Ca2+ overload, inflammation, pyroptosis, ferroptosis, apoptosis, senescence, etc. Exosomes (EXOs), as extracellular vesicles (EVs), play an important role in the material exchange and signal transmission between cells by carrying components such as proteins and RNAs. More recently, there has been a growing number of publications focusing on the protective effect of EXOs on DIC. Here, this review summarized the main mechanisms of DIC, discussed the mechanism of EXOs in the treatment of DIC, and further explored the value of EXOs as diagnostic biomarkers and therapeutic strategies for DIC.

A simple, rapid method using CE and microchip electrophoresis with (CD)-D-4 has been developed for the separation of four nonsteroidal anti-inflammatory drugs (NSAIDs) in the environmental sample. The investigated compounds were ibuprofen (IB), ketoprofen (KET), acetylsalicylic acid (ASA), and diclofenac sodium (DIC). In the present study, we applied for the first time microchip electrophoresis with (CD)-D-4 detection to the separation and detection of ASA, IB, DIC, and KET in the wastewater matrix. Under optimum conditions, the four NSAIDs compounds could be well separated in less than 1 min in a BGE composed of 20 mM His/15 mM Tris, pH 8.6, 2 mM hydroxypropyl-beta-cyclodextrin, and 10% methanol (v/v) at a separation voltage of 1000-1200 V. The proposed method showed excellent repeatability, good sensitivity (LODs ranging between 0.156 and 0.6 mg/L), low cost, high sample throughputs, portable instrumentation for mobile deployment, and extremely lower reagent and sample consumption. The developed method was applied to the analysis of pharmaceuticals in wastewater samples with satisfactory recoveries ranging from 62.5% to 118%.

Patients with Human Immunodeficiency Virus (HIV) infection are at risk of thrombotic microangiopathies (TMAs) notably thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC). Overlap between laboratory results exists resulting in diagnostic ambiguity.Routine laboratory results of 71 patients with HIV-associated TTP (HIV-TTP) and 81 with DIC with concomitant HIV infection (HIV-DIC) admitted between 2015 and 2021 to academic hospitals in Johannesburg, South Africa were retrospectively reviewed. Both the PLASMIC and the International Society of Thrombosis and Haemostasis (ISTH) DIC scores were calculated.Patients with HIV-TTP had significantly (P .001) increased schistocytes and features of hemolysis including elevated lactate dehydrogenase (LDH)/upper-limit-of-normal ratio (median of 9 (interquartile range [IQR] 5-12) vs 3 (IQR 2-5)) but unexpectedly lower fibrinogen (median 2.8 (IQR 2.2-3.4) vs 4 g/L (IQR 2.5-9.2)) and higher D-dimer (median 4.8 (IQR 2.4-8.1) vs 3.6 g/L (IQR 1.7-6.2)) levels vs the HIV-DIC cohort. Patients with HIV-DIC were more immunocompromised with frequent secondary infections, higher platelet and hemoglobin levels, more deranged coagulation parameters and less hemolysis. Overlap in scoring systems was however observed.The laboratory parameter overlap between HIV-DIC and HIV-TTP might reflect a shared pathogenesis including endothelial dysfunction and inflammation and further research is required. Fibrinogen in DIC may be elevated as an acute phase reactant and D-dimers may reflect the extensive hemostatic activation in HIV-TTP. Inclusion of additional parameters in TMA scoring systems such the LDH/upper-limit-of-normal ratio, schistocytes count and wider access to ADAMTS-13 testing may enhance diagnostic accuracy and ensure appropriate utilization of plasma.

Chemo-/radioresistance is the most important reason for the failure of glioblastoma (GBM) treatment. Reversing the chemo-/radioresistance of GBM for boosting therapeutic efficacy is very challenging. Herein, we report a significant decrease in the chemo-/radioresistance of GBM by the

Background Alongside its original diagnostic intention, the International Society on Thrombosis and Haemostasis' (ISTH) disseminated intravascular coagulation (DIC) score predicts mortality in various patient groups. Objectives We investigated whether coagulopathy quantified by the DIC score can predict 30-day mortality in patients with liver disease and low fibrinogen levels. Methods We retrospectively analyzed all patients admitted to the Vienna General Hospital between 2003 and 2014 with a fibrinogen level of Results A total of 1,333 patients were screened, and 388 of these patients (38% female, median age: 58 years, interquartile range: 48–66 years) were analyzed. The DIC-2001 (hazard ratio [HR]: 2.08, 95% confidence interval [CI]: 1.78–2.59, p Conclusion The ISTH DIC-2001 and DIC-2018 scores predicted 30-day mortality in patients with liver disease and low fibrinogen levels. The DIC score deserves further investigation in this population as it likely reflects different dimensions of the underlying disease.

Five-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody-drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available.We randomly assigned patients in a 1:1 ratio to receive up to six cycles of A+AVD or ABVD. The primary end point, modified progression-free survival, has been reported previously. The key secondary end point was overall survival in the intention-to-treat population. Safety was also assessed.A total of 664 patients were assigned to receive A+AVD and 670 to receive ABVD. At a median follow-up of 73.0 months, 39 patients in the A+AVD group and 64 in the ABVD group had died (hazard ratio, 0.59; 95% confidence interval [CI], 0.40 to 0.88; P = 0.009). The 6-year overall survival estimates were 93.9% (95% CI, 91.6 to 95.5) in the A+AVD group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Progression-free survival was longer with A+AVD than with ABVD (hazard ratio for disease progression or death, 0.68; 95% CI, 0.53 to 0.86). Fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation, and fewer second cancers were reported with A+AVD (in 23 vs. 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with A+AVD. More patients had peripheral neuropathy with A+AVD than with ABVD, but most patients in the two groups had resolution or amelioration of the event by the last follow-up.Patients who received A+AVD for the treatment of stage III or IV Hodgkin's lymphoma had a survival advantage over those who received ABVD. (Funded by Takeda Development Center Americas and Seagen; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.).

Multitype recurrent events are commonly observed in transportation studies, since commercial truck drivers may encounter different types of safety critical events (SCEs) and take different lengths of on-duty breaks in a driving shift. Bayesian nonhomogeneous Poisson process models are a flexible approach to jointly model the intensity functions of the multitype recurrent events. For evaluating and comparing these models, the deviance information criterion (DIC) and the logarithm of the pseudo-marginal likelihood (LPML) are studied and Monte Carlo methods are developed for computing these model assessment measures. We also propose a set of new concordance indices (C-indices) to evaluate various discrimination abilities of a Bayesian multitype recurrent event model. Specifically, the within-event C-index quantifies adequacy of a given model in fitting the recurrent event data for each type, the between-event C-index provides an assessment of the model fit between two types of recurrent events, and the overall C-index measures the model's discrimination ability among multiple types of recurrent events simultaneously. Moreover, we jointly model the incidence of SCEs and on-duty breaks with driving behaviors using a Bayesian Poisson process model with time-varying coefficients and time-dependent covariates. An in-depth analysis of a real dataset from the commercial truck driver naturalistic driving study is carried out to demonstrate the usefulness and applicability of the proposed methodology.

Microalgae within the Scenedesmaceae are often distinguished by spines, bristles, and other wall characteristics. We examined the dynamic production and chemical nature of bristles extruded from the poles of Tetradesmus deserticola previously isolated from microbiotic crust. Rapidly growing cells in a liquid growth medium were established in polydimethylsiloxane microfluidic chambers specially designed to maintain aerobic conditions over time within a chamber 6-12 μm deep. This geometry enabled in-focus imaging of single cells over long periods. Differential interference contrast (DIC) imaging revealed that after multiple fission of mother cells, the newly released, lemon-shaped daughter cells began extruding bristles from each pole. In some instances, the bristles became stuck to either the glass floor or polydimethylsiloxane (PDMS) walls of the chamber, and the force by which the new bristle was extruded was sufficient to propel the cells across the field of view at ~1.2 μm · h

The utility of dose escalation after positive positron emission tomography following 2 cycles of ABVD (PET2) for Hodgkin Lymphoma (HL) remains controversial. We describe the United States real-world practice patterns for PET2 positive patients.Data was collected from 15 sites on PET2 positive HL patients after receiving frontline treatment between January, 2015 and June, 2019. Descriptive analyses between those with therapy change and those continuing initial therapy were assessed.A total of 129 patients were identified; 111 (86%) were treated with ABVD therapy and 18 (14%) with an alternate regimen. At PET2 assessment, 74.4% (96/129) had Deauville score (DS) 4 and 25.6% (33/129) had DS 5. Of the 66 limited stage (LS) patients with PET2 DS score of 4/5, 77.3% (51/66) continued initial therapy and 22.7% (15/66) changed to escalated therapy. The 12-month progression-free survival (PFS) for DS 4/5 LS patients was 67.0% (95% CI; 54.9-81.7) for patients without escalation compared with 51.4% (95% CI; 30.8-85.8) for those who escalated. Of the 63 DS 4/5 patients with advanced stage (AS) disease, 76.2% (48/63) continued initial therapy and 23.8% (15/63) changed to escalated therapy. The 12-month PFS for DS 4/5 AS patients was 38.3% (95% CI: 26.3%-55.7%) for patients without escalation compared with 57.1% (95% CI: 36.3-89.9) for those with escalation.A minority of PET2 positive HL patients undergo therapy escalation and outcomes remain overall suboptimal. Improved prognostics markers and better therapeutics are required to improve outcomes for high-risk PET2 positive HL patients.

Coagulopathy is a common and serious problem in patients who received extracorporeal membrane oxygenation (ECMO), and this study evaluated whether the 2018 diffuse intravascular coagulation (DIC) score established by the International Society on Thrombosis and Hemostasis (ISTH) is associated with 90-day mortality in adult ECMO patients.A retrospective study analyzed data from adult patients receiving ECMO in our hospital from September 2018 to April 2021. Pre-ECMO DIC score and other variables were assessed and compared to predict 90-day mortality.Among 103 eligible patients, 55.3% received V-V ECMO and 44.7% received V-A ECMO. The overall 90-day mortality for study patients was 54.4%, including 45.6% in the V-V group and 65.2% in the V-A group. Multiple logistic regression analysis showed that after adjusting for sex, sepsis, and APACHE II score, pre-ECMO DIC scores in the total and V-V group predicted 90-day mortality (odds ratio(OR): 1.419, 95% confidence interval (CI): 1.101-1.828; OR: 2.562; 95% CI: 1.452-4.520). Receiver operating characteristic (ROC) curves displayed that pre-ECMO DIC score of 4 in the total and V-V group was a good predictor of 90-day mortality (area under the curve [AUC] = 0.706, 95% CI: 0.606-0.806; AUC = 0.737, 95% CI: 0.604-0.870). Kaplan-Meier curves demonstrated the 90-day mortality of patients with pre-ECMO DIC score ≥ 4 in the total and V-V group was higher than that of patients with DIC score 4 (hazard ratio [HR]: 2.821, 95% CI: 1.632-4.879; HR: 3.864, 95% CI: 1.660-8.992).The pre-ECMO ISTH DIC score was associated with 90-day mortality in adult patients undergoing ECMO, particularly in the V-V ECMO group.

Endoplasmic reticulum stress (ERS) and long non-coding RNAs (lncRNAs) are important in melanoma development and progression. This study aimed to explore the prognostic value of ERS-associated lncRNA profiles in cutaneous melanoma (CM).The Cancer Genome Atlas (TCGA) provides the raw data of CM. GSEA website was used to obtain ERS-related genes, and mRNA and LncRNA co-expression network were used to obtain ERS-related lncRNAs. A Lasso regression analysis was used to identify a prognostic risk model for the composition of ERS-related lncRNAs. Patients were divided into high- and low-risk groups based on the model's risk score. The researchers then compared the two groups' survival rates, immune infiltration, chemotherapeutic drug sensitivity, and immune checkpoint gene expression.Thirty-nine ERS-related lncRNAs were discovered to be prognostic. A prognostic risk model made up of ten ERS-related lncRNAs was discovered. Patients in the low-risk group had a better prognosis than those in the high-risk group. An examination of tumor microenvironment revealed that risk scores correlated with immune cell infiltration in eight cases. Dacarbazine, paclitaxel, and cisplatin, three chemotherapy drugs, were more sensitive in the low-risk group than in the high-risk group.This study identified a risk model of ten ERS-related lncRNAs that have significant prognostic value in CM and could help guide clinical treatment.

The primary objective of this study was to investigate the potential protective effect of Vitamin D (Vit D) on DOX induced cardio toxicity (DIC) in early breast cancer patients receiving adjuvant DOX based chemotherapy (AC). The secondary objective was to investigate the anti-inflammatory effect of Vit D by measuring serum IL-6 and its correlation with cardio toxicity.This study was carried out on 150 newly diagnosed women with breast cancer who were planned to receive four cycles of adjuvant AC chemotherapy regimen (60 mg/mVit D supplementation in Vit D group patients was associated with a significant decrease (P0.001) in serum levels of LDH, cTnT, and IL-6 compared to the control group .The present work provides a promising clinical evidence to support the cardio protective effects of Vit D against DIC through attenuating the evoked pro-inflammatory cytokines induced by DOX.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA damage sensor and contributes to both DNA repair and cell death processes. However, how PARP-1 signaling is regulated to switch its function from DNA repair to cell death remains largely unknown. Here, we found that PARP-1 plays a central role in alkylating agent-induced PARthanatic cancer cell death. Lysine demethylase 6B (KDM6B) was identified as a key regulator of PARthanatos. Loss of KDM6B protein or its demethylase activity conferred cancer cell resistance to PARthanatic cell death in response to alkylating agents. Mechanistically, KDM6B knockout suppressed methylation at the promoter of O6-methylguanine-DNA methyltransferase (MGMT) to enhance MGMT expression and its direct DNA repair function, thereby inhibiting DNA damage-evoked PARP-1 hyperactivation and subsequent cell death. Moreover, KDM6B knockout triggered sustained Chk1 phosphorylation and activated a second XRCC1-dependent repair machinery to fix DNA damage evading from MGMT repair. Inhibition of MGMT or checkpoint response re-sensitized KDM6B deficient cells to PARthanatos induced by alkylating agents. These findings provide new molecular insights into epigenetic regulation of PARP-1 signaling mediating DNA repair or cell death and identify KDM6B as a biomarker for prediction of cancer cell vulnerability to alkylating agent treatment.

Microtubule-associated proteins regulate the dynamics, organization, and function of microtubules, impacting a number of vital cellular processes. CRMPs have been shown to control microtubule assembly and axon outgrowth during neuronal differentiation. While many microtubule-associated proteins have been linked to roles in cell division and neuronal development, it is still unclear the complement that control the formation of parallel microtubule arrays in epithelial cells.Here we show through time-lapse DIC microscopy that Caenorhabditis elegans embryos homozygous for the weak loss-of-function allele unc-33(e204) progress more slowly through epidermal morphogenesis, while animals homozygous for strong loss-of-function alleles exhibit more embryonic lethality. Identification of two novel missense mutations in unc-33(e572), Val476Gly, and Ser731Thr, lead to computational approaches to determine the potential effects of these changes on UNC-33/CRMP structure. Molecular dynamics simulations show that for Asp389Asn and Arg502His, two other known missense mutations, local changes in protein-protein hydrogen bonding affect the stability of the protein. However, the Val476Gly/Ser731Thr combination does not alter the structure or energetics of UNC-33 drastically when compared to the wild-type protein.These results support a novel role for UNC-33/CRMP in C. elegans epidermal development and shed light on how individual amino acid changes cause a loss-of-function in UNC-33.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults with high metastasis rates. The O6-methylguanine DNA methyl transferase (MGMT) is involved in chemoresistance of Dacarbazine (DTIC) treatment. Our previous study found that the combination of oncolytic adenovirus H101 and DTIC in the treatment of UM cells shows a synergistic antitumor effect mainly though down-regulation of MGMT. MGMT knockdown by shRNAs increases the sensitivity of uveal melanoma cells to DTIC treatment. The protein hemostasis of MGMT is important for the antitumor effect of DTIC. Tripartite motif-containing protein 72 (TRIM72) belongs to the tripartite motif (TRIM) proteins family and was identified as a novel E3 ligase for MGMT, which interacts with and mediates the ubiquitination of MGMT. TRIM72 knockdown increases the protein levels of MGMT, while reduces the ubiquitination of MGMT. Further study indicated that MGMT is highly expressed in UM cells, and the protein levels of MGMT and TRIM72 shows a negative correlation. UM cells that ectopically expressing TRIM72 shows increased sensitivity to DTIC treatment, which is consistent with the antitumor affect exhibited by H101. These results suggest that TRIM72 is a promising therapeutic target for UM treatment.

Maternal tolerance to semi- or fully allograft conceptus is a prerequisite for the maintenance of pregnancy. Once this homeostasis is disrupted, it may result in pregnancy loss. As a potential approach to prevent pregnancy loss, targeting decidual immune cells (DICs) at the maternal-fetal interface has been suggested. Although the phenotypic features and functions of DIC have been extensively profiled, the regulatory pathways for this unique immunological adaption have yet to be elucidated. In recent years, a pivotal mechanism has been highlighted in the area of immunometabolism, by which the changes in intracellular metabolic pathways in DIC and interaction with the adjacent metabolites in the microenvironment can alter their phenotypes and function. More inspiringly, the manipulation of metabolic profiling in DIC provides a novel avenue for the prevention and treatment of pregnancy loss. Herein, this review highlights the major metabolic programs (specifically, glycolysis, ATP-adenosine metabolism, lysophosphatidic acid metabolism, and amino acid metabolism) in multiple immune cells (including decidual NK cells, macrophages, and T cells) and their integrations with the metabolic microenvironment in normal pregnancy. Importantly, this perspective may help to provide a potential therapeutic strategy for reducing pregnancy loss via targeting this interplay.

Hodgkin variant Richter transformation (HvRT) is a rare and challenging complication of chronic lymphocytic leukaemia (CLL) for which information on prognostic factors and treatment approaches remain limited. We analysed characteristics and survival outcomes of a population-based cohort of 32 patients with HvRT identified in British Columbia over a 40-year period. Median interval from CLL diagnosis to HvRT was 5.6 years (range, 0-33.6), with five cases diagnosed concurrently. Most patients (80%) had treatment for CLL prior to HvRT. Median age at HvRT was 71 years (range, 51-86) and the majority of patients had high-risk disease, including stage 3-4 in 87% and International Prognostic Score (IPS) ≥ 4 in 65%. Two-year progression-free (PFS) and overall survival (OS) from HvRT were 47% (95% CI: 29%-64%) and 57% (95% CI: 38%-72%), respectively. OS from HvRT was significantly worse in those with anaemia (p = 0.02), elevated lactate dehydrogenase (p = 0.04), high IPS (p = 0.04), and worse performance status (p = 0.001). For those treated with curative-intent ABVD/ABVD-like therapy, 2-year PFS and OS were 70% (95% CI: 45%-85%) and 74% (95% CI: 49%-89%), respectively. In this real-world population-based cohort, HvRT was associated with poor clinical outcomes overall; however, those able to tolerate curative-intent therapy had similar survival to older patients with de novo HL.

Glioblastomas with multiple foci at presentation (mGBMs) account for 2–35% of all GBMs. mGBMs have limited existing data and no standardized treatment. This study aims to determine their incidence, demographic and clinical features, outcome, and prognostic factors in terms of overall survival. We performed a monocentric retrospective study, reviewing patients treated at the Istituto Oncologico Veneto. Inclusion criteria were: new diagnosis of GBM and presence of multiple lesions on pre-treatment MRI. ECOG PS was used to evaluate clinical condition, RANO criteria for radiological assessment, and CTCAE v5.0 for treatment-related adverse events. The incidence of newly diagnosed mGBM was 7.2% and the study population consisted of 98 patients. Median age was 63 years, M:F ratio of 1.8:1, and a surgical approach was undertaken in 73 patients (mostly partial resection). MGMT was methylated in 47.5%, and 82 patients received active oncological treatment (65.9% radiotherapy plus temozolomide (RT + TMZ)). The disease control rate with RT + TMZ was 63%. Median OS of the entire study population was 10.2 months (95% CI 6.6–13.8), and median PFS was 4.2 months (95% CI 3.2–5.2). The ECOG PS, the extent of resection, and the RT + TMZ were significant prognostic factors in the univariate analysis for OS, but only the RT + TMZ was a significant independent OS predictor in the multivariate analysis (HR = 3.1, 95% IC 1.3–7.7, p = 0.014). The incidence of mGBM is not rare. RT + TMZ is confirmed to be an independent prognostic factor for survival and a safe and effective treatment. When feasible, RT + TMZ should be considered as a possible first-line treatment. The role of the extent of resection is still unclear.

The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)–deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment. Significance: MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments. See related commentary by Willis and Overman, p. 1612. This article is highlighted in the In This Issue feature, p. 1599

Background: Melanoma, also known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin but may rarely occur in the mouth, intestines or, eye. This study aims to examine the expression of the mammalian target of rapamycin (mTOR)/70S6K signaling pathway in melanoma cancer. Methods: The B16F10 cell line treated with dacarbazine IC50 and different concentrations of metformin (0.5, 2, and 8 mM) for 24 hr and mTOR and 70S6k proteins expression were examined by western blotting. Cell viability was measured by MTT assay. Results: Western blot analysis showed that after different concentrations of metformin and dacarbazine treatments, the mTOR and 70S6K protein expression significantly (P Conclusion: Metformin-induced repression of mTOR/70S6k axis activity disrupts B16F10 growth. Thus, we believe that combination therapy may be a suitable potential therapeutic target for melanoma cancer.

Cancer-associated hypercalcemia commonly occurs through abnormal secretions of parathyroid hormone-related protein (PTHrP) from cancer cells. Several cases of PTHrP-producing melanoma causing hypercalcemia have been reported; however, effective management of PTHrP-producing BRAF wild-type melanoma causing hypercalcemia after immune checkpoint inhibitor (ICI) failure is unclear. We report a case of PTHrP-producing BRAF wild-type melanoma leading to oncological emergency by hypercalcemia that was successfully treated with dacarbazine after ICI failure. A 65-year-old Japanese woman had advanced BRAF wild-type melanoma that was refractory to ICI, and then led to hypoxia through exacerbated lung metastases and pleural effusion. Moreover, hypercalcemia appeared in parallel with increase of the serum PTHrP level. Dacarbazine was administered, and after the first administration, the pleural effusion was gradually decreased and hypoxia rapidly disappeared, and the serum calcium and PTHrP levels were improved within normal limits. Dacarbazine after ICI failure is potentially a useful option for oncological emergency due to progression of BRAF wild-type melanoma including PTHrP-producing types. Dacarbazine should be reevaluated as a therapeutic option for oncological emergency in patients with BRAF wild-type melanoma after ICI failure.

Doxorubicin (DOX), a commonly used antitumor agent, is often accompanied by its dosage-dependent cardiotoxicity, which incorporates ferroptosis in its pathogenesis. Protein arginine methyltransferase 4 (PRMT4) is a transcription regulator involved in the modulation of oxidative stress and autophagy, but its role in DOX-induced cardiomyopathy (DIC) and ferroptosis remains elusive. Herein, we aimed to investigate the involvement and the underlying mechanisms of PRMT4 in the pathogenesis of DIC. Our present study revealed that the expression level of PRMT4 was markedly decreased in DOX-treated cardiomyocytes. Interestingly, it is noted that PRMT4 overexpression accelerated ferroptosis to aggravate DIC, while its gene disruption or pharmaceutical inhibition exhibited the opposite effect. Mechanistically, our observation demonstrated that PRMT4 interacted with the nuclear factor erythroid 2-related factor 2 (Nrf2) to promote its enzymatic methylation, which restricted the nuclear translocation of Nrf2 and subsequently suppressed the transcription of glutathione peroxidase 4 (GPX4). Importantly, the detrimental role of PRMT4 in DOX-induced cardiomyocyte ferroptosis was abolished by Nrf2 activation or Fer-1 administration. Collectively, our data reveal that PRMT4 inhibits Nrf2/GPX4 signaling to accelerate ferroptosis in DIC, suggesting that targeting PRMT4 may present as a potential preventive strategy against the development of DIC.

PURPOSE The AHL2011 study (ClinicalTrials.gov identifier: NCT01358747 ) demonstrated that a positron emission tomography (PET)-driven de-escalation strategy after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) provides similar progression-free survival (PFS) and overall survival (OS) and reduces early toxicity compared with a nonmonitored standard treatment. Here, we report, with a prolonged follow-up, the final study results. METHODS Patients with advanced Hodgkin lymphoma (stage III, IV, or IIB with mediastinum/thorax ratio > 0.33 or extranodal involvement) age 16-60 years were prospectively randomly assigned between 6 × BEACOPP and a PET-driven arm after 2 × BEACOPP delivering 4 × ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in PET2– and 4 × BEACOPP in PET2+ patients. PET performed after four cycles of chemotherapy had to be negative to complete the planned treatment. RESULTS In total, 823 patients were enrolled including 413 in the standard arm and 410 in the PET-driven arm. With a 67.2-month median follow-up, 5-year PFS (87.5% v 86.7%; hazard ratio [HR] = 1.07; 95% CI, 0.74 to 1.57; P = .67) and OS (97.7% in both arms; HR = 1.012; 95% CI, 0.50 to 2.10; P = .53) were similar in both randomization arms. In the whole cohort, full interim PET assessment predicted patients' 5-year PFS (92.3% in PET2–/PET4–, 75.4% [HR = 3.26; 95% CI, 18.3 to 5.77] in PET2+/PET4– and 46.5% [HR = 12.4; 95% CI, 7.31 to 19.51] in PET4+ patients, respectively; P < .0001) independent of international prognosis score. Five-year OS was also affected by interim PET results, and PET2+/PET4– patients (93.5%; HR = 3.3; 95% CI, 1.07 to 10.1; P = .036) and PET4+ patients (91.9%; HR = 3.756; 95% CI, 1.07 to 13.18; P = .038) had a significant lower OS than PET2–/PET4– patients (98.2%). Twenty-two patients (2.7%) developed a second primary malignancy, 13 (3.2%) and 9 (2.2%) in the standard and experimental arms, respectively. CONCLUSION The extended follow-up confirms the continued efficacy and favorable safety of AHL2011 PET-driven strategy, which is noninferior to standard six cycles of BEACOPP. PET4 provides additional prognostic information to PET2 and allows identifying patients with particularly poor prognosis.

Doxorubicin is a commonly used chemotherapeutic drug, but its use is limited by doxorubicin-induced cardiotoxicity (DIC), which can lead to irreversible heart failure and death. A missense variant rs2229774 (p.S427L) in the retinoic acid receptor gamma (RARG) gene is associated with increased susceptibility to DIC, but the precise mechanism underlying this association is incompletely understood. We performed molecular dynamic simulations to determine the effect of this variant on RARG structure and then validated these predictions using CRISPR-Cas9-genome-edited, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We found that this variant leads to reduced activation of its target genes in response to doxorubicin, including gene pathways involved in DNA repair and consequently an inability to mediate DNA repair after exposure to doxorubicin. Our findings establish a role of RARG p.S427L in attenuating DNA repair in DIC and provide insight into the pathogenesis of this cardiotoxic effect.

Acute right ventricular (RV) failure is common in patients hospitalized with COVID-19. Compared to the conventional echocardiographic parameters, right ventricular longitudinal strain (RVLS) is more sensitive and accurate for the diagnosis of RV systolic dysfunction.Our purpose was to investigate the sustained RV dysfunction echo-quantified by RVLS in patients recovered from severe COVID-19. Furthermore, we aimed to assess whether disseminated intravascular coagulation (DIC) has a key role to predict the impaired RV strain.Of 198 consecutive COVID-19 patients hospitalized from March 1, 2020, to April 15, 2020, 45 selected patients who survived from severe COVID-19 were enrolled in the study and referred to our echo-lab for transthoracic echocardiography 6-months after discharge. RVLS was calculated as the mean of the strain values of RV free wall. DIC was defined with a validated scoring system: DIC score equal to or more than 5 is compatible with overt-DIC. Categories of acute respiratory distress syndrome (ARDS) were defined based on PaOA total 26 of 45 patients showed impaired RVLS at 6-months' follow-up. DIC score was significantly higher in patients with worse RVLS than in those with better RVLS (4.8 ± .5 vs. 3.6 ± .6, p =.03). Stages of ARDS did not modulate this relationship. Finally, overt-DIC results the only independent predictor of sustained RV dysfunction (OR 1.233, 95% CI 1.041-1.934, p =.043).Sustained RV impairment frequently occurs in patients recovered from severe COVID-19. DIC plays a key role, resulting in an independent predictor of sustained RV dysfunction.

Children with relapsed/refractory central nervous system (CNS) tumors require novel combinations of therapies. Irinotecan and temozolomide (IT) is a frequently used therapy with an established toxicity profile. Bevacizumab is an anti-VEGF monoclonal antibody with demonstrated activity in CNS tumors. Therefore, the combination of these agents has therapeutic potential in CNS tumors. The objective of this study was to determine the maximum tolerated dose (MTD) of escalating dose IT combined with a fixed dose of bevacizumab (BIT) in children with relapsed/refractory CNS tumors.A phase I trial was performed in a 3 + 3 design. Therapy toxicities and radiologic responses to treatment were described.One hundred eighty cycles of therapy were administered to 26 patients. The MTD of BIT was dose level 1, (bevacizumab 10 mg/kg on days 1 and 15, irinotecan 125 mg/mAt the MTD, BIT therapy was well tolerated, and prolonged treatment courses of up to 24 cycles were feasible, with radiographic responses observed. Further evaluation is needed for efficacy in a phase II trial (NCT00876993, registered April 7, 2009, www.gov ).

Despite multiple randomized trials, variation in practice remains regarding the most effective treatment for early-stage, favorable-risk Hodgkin lymphoma. With increasing emphasis on alternative payment models, we investigate the cost-effectiveness of chemotherapy alone versus combined modality therapy (CMT).A Markov model was formed to compared 2 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) to 2 cycles of ABVD followed by 20 Gy in 10 fractions involved-site radiation therapy. Modalities were compared using the incremental cost-effectiveness ratio, with effectiveness measured in quality-adjusted life years (QALYs) and evaluated with a willingness to pay a threshold of $100,000 per QALY gained.The base case analysis showed that CMT is cost-effective compared with ABVD alone, with an incremental cost-effectiveness ratio of $8028 per QALY gained and an incremental cost of $236 gaining 0.029 QALYs. On sensitivity analyses, the results were the most sensitive to changes in recurrence rates. If the recurrence rate differences were ≥6%, CMT was cost-effective.CMT is a cost-effective strategy for early-stage, favorable-risk Hodgkin lymphoma based on currently available evidence. However, small variations in recurrence-rate estimates dramatically affect strategy cost-effectiveness.

Acute promyelocytic leukemia (APL) differs from other forms of acute myeloid leukemia (AML), including coagulopathy, hemorrhage, disseminated intravascular coagulation (DIC), and treatment success with all-trans retinoic acid (ATRA). Despite ATRA, early deaths (ED) are still common in APL. Here, we evaluated factors associated with ED and applicability of scoring systems used to diagnose DIC. Ninety-one APL patients (55 females, 36 males, and median age 40 years) were included. ED was defined as deaths attributable to any cause between day of diagnosis and following 30th day. DIC was assessed based on DIC scoring system released by the International Society of Thrombosis and Hemostasis (ISTH) and Chinese Diagnostic Scoring System (CDSS). Patients' median follow-up time was 49.2 months, and ED developed in 14 (15.4% of) cases. Patients succumbing to ED had higher levels of the Eastern Cooperative Oncology Group Performance Status (ECOG PS), lactate dehydrogenase (LDH), and ISTH DIC, and lower fibrinogen levels (p0.05). In multivariate Cox regression analysis, age55 and ECOG PS ≥2 rates were revealed to be associated with ED. Based on ISTH and CDSS scores, DIC was reported in 47.3 and 58.2% of the patients, respectively. Despite advances in APL, ED is still a major obstacle. Besides the prompt recognition and correction of coagulopathy, those at high ED risk are recommended to be detected rapidly. Implementation of local treatment plans and creating awareness should be achieved in hematological centers. Common utilization of ATRA and arsenic trioxide (ATO) may be beneficial to overcome ED and coagulopathy in APL patients.

Hemostatic disturbances are common in patients with cirrhosis. Few studies have evaluated the prognostic role of hemostatic parameters in cirrhosis with acute decompensation. This study aims to determine the prognostic ability of standard hemostatic parameters in hospitalized cirrhotic patients with acute decompensation. Cirrhotic patients admitted with acute decompensation were prospectively enrolled. Hemostatic parameters were determined within 24 h, and the DIC (disseminated intravascular coagulation) score was calculated based on platelet count, prothrombin time (PT), fibrinogen, and D- dimer. New onset of in-hospital major bleeding and 90-day mortality were assessed. Eighty-nine patients were included (MELD 13.6 ± 5.7). The indications of admission were infection (38.2%), and portal hypertension-related bleeding (31.5%). 14.6% developed in-hospital major bleeding, and 90-day mortality rate was 21.3%. Major bleeding group and 90-day nonsurvivors had significantly higher activated partial thromboplastin time (aPTT), PT, and DIC score. The 90-day mortality rate was higher in major bleeding group (46.2 vs. 17.1%, P = 0.029). By multivariate logistic regression analysis, DIC score was associated with 90-day mortality. The AUROC of DIC score for 90-day mortality prediction was significantly higher than of MELD score (0.78 vs. 0.59, P = 0.04). DIC score at least 4 predicted 90-day mortality with a sensitivity of 88.9%. The cumulative 90-day survival was significantly lower in patients with DIC score at least 4 (57.2 vs. 93.6%, P = 0.0003). The development of in-hospital major bleeding significantly increases mortality in cirrhotic patients with acute decompensation. The DIC score within 24 h can be used as a simple and reliable predictor for 90-day mortality in these patients.

Thin von Frey monofilaments are a clinical tool used worldwide to assess touch deficits. One’s ability to perceive touch with low-force monofilaments (0.008 – 0.07 g) establishes an absolute threshold and thereby the extent of impairment. While individual monofilaments bend at defined forces, there are no empirical measurements of the skin surface’s response. In this work, we measure skin surface deformation at light-touch perceptual limits, by adopting an imaging approach using 3D digital image correlation (DIC). Generating point cloud data from three cameras surveilling the index finger pad, we reassemble and stitch together multiple 3D surfaces. Then, in response to each monofilament’s indentation over time, we quantify strain across the skin surface, radial deformation emanating from the contact point, penetration depth into the surface, and area between 2D cross-sections. The results show that the monofilaments create distinct states of skin deformation, which align closely with just noticeable percepts at absolute detection and discrimination thresholds, even amidst variance between individuals and trials. In particular, the resolution of the DIC imaging approach captures sufficient differences in skin deformation at threshold, offering promise in understanding the skin’s role in perception.

Background/Aim: Advanced gastric cancer (AGC) rarely presents with disseminated intravascular coagulation (DIC) at the time of diagnosis. Chemotherapy should be selected in consideration of hematological toxicities because these patients are at high risk of hemorrhagic complications. The leucovorin, fluorouracil, and oxaliplatin (FOLFOX) regimen is an effective and less toxic regimen for patients with AGC and poor performance status. Patients and Methods: The present study assessed overall survival of all patients receiving first-line chemotherapy with and without DIC using Kaplan-Meier methods and examined the clinicopathological factors, DIC parameters, response, and survival of five patients with AGC and DIC who received FOLFOX in the first-line setting between February 2017 and February 2020. Results: Among the patients, four patients (80%) recovered from DIC after a median of 12 days of FOLFOX therapy (range=12-25), and their platelet count gradually increased within 1 week after the start of chemotherapy. The median progression-free survival and overall survival were 46 (range=22-296) and 115 days (range=83-324), respectively. No patients experienced adverse events necessitating treatment discontinuation, including gastrointestinal bleeding and thrombocytopenia. Moreover, all patients received second-line treatment after progression, and one patient exhibited improvement of DIC symptoms following nab-paclitaxel and ramucirumab treatment. Conclusion: FOLFOX therapy is well tolerated and effective in patients with AGC initially presenting with DIC and subsequent second-line treatment might be crucial for better prognosis.

Thymus and activation-regulated chemokine (TARC) is expressed on Reed-Sternberg cells of patients with classical Hodgkin lymphoma (HL) and may serve as a marker in response assessment. In our study, we correlated serum TARC levels with early response to treatment measured by PET/CT in 19 newly diagnosed patients with HL who received ABVD (Adriblastin, Bleomycin, Vinblastine, Dacarbazine) regimen. Finally, 17 patients were analyzed and six of them (35%) achieved PET/CT negativity defined as Deauville (D) 1 or 2 after 2 cycles of ABVD; 11 pts (65%) had D3 on PET/CT. None of the patients presented D 4/5. Median serum TARC levels at diagnosis were significantly higher when compared with healthy controls: 5718 pg/ml vs 76.1 pg/ml (p p = 0.049. There was a tendency to higher baseline serum TARC levels in patients with an increased LDH (lactate dehydrogenase) activity (p = 0.08) and in those who progressed when compared with those who maintained response (p = 0.09). Serum TARC levels decrease after chemotherapy and may serve as a marker of response assessment.

Background Mucosal melanoma is rare and has distinct clinical and genetic features. Even with advances in targeted and immune therapies, the survival of patients with advanced or recurrent mucosal melanomas remains poor. The standard treatment remains controversial and we conducted this real-world study aimed to explore continuous intravenous recombinant human endostatin (Rh-endostatin) infusion plus chemotherapy in this population in the first-line setting. Methods Overall, 43 patients with advanced or recurrent mucosal melanoma treated at Fudan University Shanghai Cancer Center between April 2017 and August 2020 were retrospectively included. Patients received dacarbazine plus cisplatin or temozolomide plus cisplatin per the investigators' preference. Rh-endostatin (105 mg/m2) was administered with continuous infusion for 168 h (Civ 168 h). Results Of the 43 patients, 72.1% had metastatic disease, and the most common primary site was the gastrointestinal tract (51.2%). The most commonly observed mutations were NRAS (23.1%), BRAF (7.7%) and CKIT mutations (5.1%). An objective response was observed in 12 (30.0%) of the 40 evaluable patients, and disease control was achieved in 31 (77.5%) patients. With a median follow-up of 17.6 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively. Additionally, high lymphocyte-to-monocyte ratio (LMR) (p = 0.023, HR 0.29, 95% CI: 0.10-0.84) and BRAF/KIT/RAS mutation (p = 0.028, HR 0.24, 95% CI: 0.07-0.86) were independently correlated with prolonged OS. Toxicity was manageable overall. Conclusion Continuous Rh-endostatin infusion plus chemotherapy was effective and safe for the treatment of advanced or recurrent mucosal melanoma. High LMR was correlated with favorable PFS and OS in this patient population.

Background Hypomagnesemia reportedly has significant associations with poor clinical outcomes such as increased mortality and septic shock in patients with sepsis. Although the mechanism underlying these outcomes mostly remains unclear, some experimental data suggest that magnesium deficiency could potentiate coagulation activation in sepsis. However, in sepsis, the association between serum magnesium levels and coagulopathy, including disseminated intravascular coagulation (DIC), remains unknown. Thus, we aimed to investigate the relationship between serum magnesium levels and coagulation status and the association between hypomagnesemia and DIC in patients with sepsis. Methods This retrospective observational study was conducted at the intensive care unit (ICU) of a university hospital from June 2011 to December 2017. Patients older than 19 years who met the Sepsis-3 definition were included. We categorized patients into three groups according to their serum magnesium levels: hypomagnesemia (< 1.6 mg/dL), normal serum magnesium level (1.6–2.4 mg/dL), and hypermagnesemia (> 2.4 mg/dL). We investigated the association between serum magnesium levels and overt DIC at the time of ICU admission according to the criteria of the International Society on Thrombosis and Haemostasis. Results Among 753 patients included in this study, 181 had DIC, 105 had hypomagnesemia, 552 had normal serum magnesium levels, and 96 had hypermagnesemia. Patients with hypomagnesemia had a more activated coagulation status indicated by lower platelet counts, lower fibrinogen levels, higher prothrombin time-international normalized ratios, higher thrombin-antithrombin complex, and more frequent DIC than those with normal serum magnesium levels and hypermagnesemia (DIC: 41.9% vs. 20.6% vs. 24.0%, P < 0.001). The coagulation status in patients with hypomagnesemia was more augmented toward suppressed fibrinolysis than that in patients with normal serum magnesium levels and hypermagnesemia. Multivariate logistic regression revealed that hypomagnesemia was independently associated with DIC (odds ratio, 1.69; 95% confidence interval, 1.00–2.84; P = 0.048) after adjusting for several confounding variables. Conclusions Patients with hypomagnesemia had a significantly activated coagulation status and suppressed fibrinolysis. Hypomagnesemia was independently associated with DIC in patients with sepsis. Therefore, the treatment of hypomagnesemia may be a potential therapeutic strategy for the treatment of coagulopathy in sepsis.

Structural health monitoring (SHM) techniques often require a large number of sensors to evaluate and monitor the structural health. In this paper, we propose a deep neural network (DNN)-based SHM method for accurate crack detection and localization in real time using a small number of strain gauge sensors and confirm its feasibility based on experimental data. The proposed method combines a DNN model with principal component analysis (PCA) to predict the strain field based on the local strains measured by strain gauge sensors located rather sparsely. We demonstrate the potential of the proposed technique via a cyclic 4-point bending test performed on a composite material specimen without cracks and seven specimens with different lengths of cracks. A dataset containing local strains measured with 12 strain gauge sensors and strain field measured with a digital image correlation (DIC) device was prepared. The strain field dataset from DIC is converted to a smaller dimension latent space with a few eigen basis via PCA, and a DNN model is trained to predict principal component values of each image with 12 strain gauge sensor measurements as input. The proposed method turns out to accurately predict the strain field for all specimens considered in the study.

The InPOG-HL-15-01, a multicentric prospective study, used a risk-stratified and response-based approach with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) backbone to treat children and adolescents with newly diagnosed Hodgkin lymphoma (HL) and reduce the use of radiation therapy (RT). Children/adolescents with bulky disease or inadequate response at early response assessment (ERA) after two cycles of chemotherapy were assigned to receive RT. For ERA, positron emission tomography computed tomography (PET-CT) was recommended but not mandatory in view of limited access. This study aimed to compare the impact of using contrast-enhanced computed tomography (CECT) and PET-CT on treatment decisions and outcomes.396 patients were enrolled and 382 had an ERA at the assigned time point. Satisfactory response was defined as Deauville score 3 or less for patients undergoing PET-CT and complete response (CR)/very good partial response (VGPR) for patients undergoing CECT. Outcomes of interest incorporate 5 year event-free survival (EFS), EFS including abandonment (EFSa), and overall survival (OS).At ERA, satisfactory response was documented in 277 out of 382 (72.5%) participants and this was significantly higher in PET-CT (151 out of 186, 81.2%) as compared with CECT-based assessments (126 out of 196, 64.3%) respectively (p value .001). Amongst the 203 patients with nonbulky disease (wherein the indication for RT was entirely dependent on ERA), 96 out of 114 (84.2%) and 61 out of 89 (68.5%) patients achieved a satisfactory response according to the PET-CT and CECT (p value = .008) respectively and hence a lesser proportion of patients in the PET-CT arm received RT. Despite a lower usage of RT the 5 year OS of both groups, ERA based on CECT (91.8%) versus PET-CT (94.1%) was comparable (p value = .391) and so was the 5 year EFS (86.7 vs. 85.5%, p value = .724).Use of PET-CT as the modality for ERA is more likely to indicate a satisfactory response as compared with CECT and thereby decreases the need for RT in response-based treatment algorithm for HL-afflicted children. The reduction in the application of RT did not impact the overall outcome and plausibly would lower the risk of delayed toxic effects.

Background Placental abruption (PA) with intrauterine fetal death (IUFD) is associated with a high risk of postpartum hemorrhage (PPH) resulting from severe disseminated intravascular coagulation (DIC). Therefore, blood products that are sufficient for coagulation factor replacement must be prepared, and delivery should occur at referral medical institutions that are equipped with sufficient blood products and emergency transfusion protocols. We retrospectively reviewed the records of patients with PA and IUFD (PA-IUFD) to identify possible factors that may indicate the need for early blood transfusion and investigated whether the Japanese scoring system for PPH can be applied in such cases. Methods We used a database of 16,058 pregnant patients who delivered at Yokohama City University Medical Center between January 2000 and February 2016. Thirty-three patients were diagnosed with PA-IUFD before delivery and categorized into two groups–blood transfusion and non-transfusion–to compare the maternal characteristics and pregnancy outcomes. Results In patients with PA-IUFD, the transfusion group exhibited significantly more blood loss; lower fibrinogen levels and platelet counts; higher levels of fibrin degradation products (FDP), D-dimer, and prothrombin time; and a tendency for tachycardia on admission, compared to the non-transfusion group. Many patients in the transfusion group had normal fibrinogen levels on admission but later displayed markedly decreased fibrinogen levels. The Japan Society of Obstetrics and Gynecology (JSOG) DIC score was significantly higher in the transfusion than in the non-transfusion group. Conclusions In PA-IUFD, the fibrinogen level, platelet count, D-dimer, FDP, heart rate, and JSOG DIC score on admission may indicate the need for blood transfusion. However, even with normal fibrinogen levels on admission, continuous monitoring is indispensable for identifying progressive fibrinogen reductions in patients with PA-IUFD.

Recombinant antithrombin gamma (rAT) is reported as an effective drug for patients with disseminated intravascular coagulation (DIC) in Japan. As the appropriate dose and targeted AT activity remain unknown, this study aimed to determine these aspects for sepsis-induced DIC. Thirty-one patients with septic shock and DIC with AT levels

To explore the effect of setting up an internal-cross disciplinary team (ICDT) in the intensive care unit (ICU) on a new model of overall treatment for patients with chronic critical illness (CCI).A 60-year-old male patient with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) admitted to ICU in the Second Affiliated Hospital of Fujian Medical University was introduced. The role of ICDT composed of physicians, nurses, respiratory therapists, physiotherapists, clinical dietitians and patients' family members in ventilator withdrawal and super-early rehabilitation was analyzed in this case.The patient was diagnosed as AECOPD, type II aspiration penumonia respiratory failure, septic shock. The ICDT in ICU carried out early rehabilitation treatment for the patient on the basis of traditional infection control and supportive treatment. Under the care of the ICDT, peripheral blood white blood cell count (WBC), neutrophil count (NEU), procalcitonin (PCT), arterial partial pressure of carbon dioxide (PaCOICDT cooperation is very important for monitoring and treatment of CCI patients, which is beneficial to the super-early rehabilitation and prognosis improvement of critically ill patients.

Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomyopathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DIC. Here, we showed that DOX accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, DOX disrupted heme synthesis by decreasing the abundance of 5'-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cultured cardiomyocytes. Alas1 overexpression prevented this outcome. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing DOX-induced ferroptosis and DIC. Our findings reveal that the accumulation of DOX and iron in mitochondria cooperatively induces ferroptosis in cardiomyocytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC.

Background More than 90% of the adult population globally is chronically infected by the Epstein–Barr virus (EBV). It is well established that EBV is associated with a number of malignancies, and advances in knowledge of EBV-related malignancies are being made every year. Several studies have analysed the global epidemiology and geographic distribution of EBV-related cancers. However, most have only described a single cancer type or subtype in isolation or limited their study to the three or four most common EBV-related cancers. This review will present an overview on the spectrum of cancers linked to EBV based on observations of associations and proportions in the published literature while also using these observations to estimate the incidence and mortality burden of some of these cancers. Method We have reviewed the literature on defining features, distribution and outcomes across six cancers with a relatively large EBV-related case burden: Nasopharyngeal carcinoma (NPC), Gastric carcinoma (GC), Hodgkin lymphoma (HL), Burkitt lymphoma (BL), Diffuse large B-cell lymphoma (DLBCL) and Extranodal NK/T-cell lymphoma, Nasal type (ENKTL-NT). We retrieved published region-specific EBV-related case proportions for NPC, GC, HL and BL and performed meta-analyses on pooled region-specific studies of EBV-related case proportions for DLBCL and ENKTL-NT. We match these pooled proportions with their respective regional incidence and mortality numbers retrieved from a publicly available cancer database. Additionally, we also reviewed the literature on several other less common EBV-related cancers to summarize their key characteristics herein. Conclusion We estimated that EBV-related cases from these six cancers accounted for 239,700–357,900 new cases and 137,900–208,700 deaths in 2020. This review highlights the significant global impact of EBV-related cancers and extends the spectrum of disease that could benefit from an EBV-specific therapeutic.

Lung lesions of Hodgkin's lymphoma (HL) are rare and difficult to diagnose by nonsurgical biopsy. We herein present the case of a 72‐year‐old Japanese male who presented with accumulation of lung infiltrates and masses bilaterally on the lungs for 3 years. Although transbronchial lung biopsy (TBB) and computed tomography‐guided biopsy were conducted several times, his diagnosis remained inconclusive. On further deterioration of lung lesions, the patient was transferred to our hospital. Positron emission tomography revealed increased accumulation in the bilateral lungs and right supraclavicular lymph nodes. Surgical biopsy of the lymph node was performed. He was finally diagnosed with HL and underwent chemotherapy with doxorubicin, vinblastine, dacarbazine, and brentuximab vedotin. After chemotherapy, the lung lesion showed significant regression. A literature review indicated that the diagnostic success rate of TBB was low (18.5%) in cases of lung lesions in HL., Here, we report a case of undiagnosed HL with lung lesions despite multiple TBBs. Our literature review indicated that the diagnostic success rate of TBB was low (18.5%) in cases of lung lesions in HL. Surgical biopsy should be considered early to avoid a delay in diagnosis because the diagnostic ability of TBB for HL patients with lung lesions is limited.