BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

Lymphomas represent one of the most common malignant diseases in young men and an important issue is how treatments will affect their reproductive health. It has been hypothesized that chemotherapies, similarly to environmental chemicals, may alter the spermatogenic epigenome. Here, we report the genomic and epigenomic profiling of the sperm DNA from a 31-year-old Hodgkin lymphoma patient who faced recurrent spontaneous miscarriages in his couple 11-26 months after receiving chemotherapy with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). In order to capture the potential deleterious impact of the ABVD treatment on mutational and methylation changes, we compared sperm DNA before and 26 months after chemotherapy with whole-genome sequencing (WGS) and reduced representation bisulfite sequencing (RRBS). The WGS analysis identified 403 variants following ABVD treatment, including 28 linked to genes crucial for embryogenesis. However, none were found in coding regions, indicating no impact of chemotherapy on protein function. The RRBS analysis identified 99 high-quality differentially methylated regions (hqDMRs) for which methylation status changed upon chemotherapy. Those hqDRMs were associated with 87 differentially methylated genes, among which 14 are known to be important or expressed during embryo development. While no variants were detected in coding regions, promoter regions of several genes potentially important for embryo development contained variants or displayed an altered methylated status. These might in turn modify the corresponding gene expression and thus affect their function during key stages of embryogenesis, leading to potential developmental disorders or miscarriages.
Humans ; Male ; Hodgkin Disease/drug therapy* ; Adult ; DNA Methylation/drug effects* ; Bleomycin/therapeutic use* ; Spermatozoa/metabolism* ; Vinblastine/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Abortion, Habitual/genetics* ; Doxorubicin/therapeutic use* ; Dacarbazine/therapeutic use* ; Female ; Pregnancy

OBJECTIVE: Utilize high-resolution chromosome analysis and microarray detection to determine the genetic etiology of infertility of a 32-year old female patient. METHODS: The peripheral blood of the patient was cultured for high-resolution chromosome G and C banding karyotype analysis, and then 750K SNP-Array chip detection was performed. RESULTS: Karyotype analysis results showed that the patient's karyotype was 45,XX,-13 [7]/46,XX,r(13) (p13q34) [185]/46,XX,dic r(13;13)(p13q34;p13q34) [14]/ 47,XX,+der(13;13;13;13) (p13q34;p13q34;p13q34; p13q34), dic r(13;13) [1]/ 46,XX [3]. The microarray results showed that the patient had a 3.3 Mb deletion in the 13q34 segment of chromosome 13, which may be related to infertility. CONCLUSION Infertility of the patient reported in this article may be related to the deletion of chromosome segment (13q34-qter).
Adult ; Chimera ; Chromosome Banding ; Chromosome Deletion ; Chromosome Disorders/genetics* ; Dacarbazine ; Female ; Humans ; Infertility/genetics* ; Ring Chromosomes

Objective: To investigate the pathological characteristics and clinical prognosis of nodular sclerosis grade 2 of classic Hodgkin's lymphoma (cHL-NS2) in our cancer center. Methods: A retrospective collection of 23 cases of cHL-NS2 admitted in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from July 2008 to April 2019 was performed. Fifty-five cases of nodular sclerosis grade 1 of classical Hodgkin's lymphoma (cHL-NS1) during the same period were selected as control group. Survival curves were plotted using the Kaplan-Meier method, and Cox regression model was used to analyze the influencing factors for survival. Results: The median age of 23 cases of cHL-NS2 was 30 years old. Five cases had extra nodal invasion, and 19 cases were Ⅰ-Ⅱ stage based on Ann Arbor system. The pathological morphology of cHL-NS2 showed that the lymph node structure was completely destroyed and was divided into nodules by thick collagen. The tumor cells in the nodules were abundant and proliferated in sheets. The boundaries between the tumor cells were not clear. The incidence of tumor necrosis in cHL-NS2 was 43.5% (10/23), which was significantly higher than 18.2% (10/55) in cHL-NS1 (P=0.040). The 3-year progression-free survival (PFS) rate of patients in the cHL-NS2 group was 58.1%, which was significantly lower than 89.7% in the cHL-NS1 group (P=0.002). In all of 78 cases, the 3-year PFS rate of patients who did not obtain complete response (CR) was 67.1%, which was significantly lower than 92.2% in patients who achieved CR (P=0.030). Multivariate Cox regression analysis demonstrated that both cHL-NS2 and failure to obtain CR by first-line treatment were independent indicators for short PFS time (P<0.05). Conclusions: In cHL-NS2, the morphology of tumor cells are diverse, and tumor necrosis can be easily found. Under the current first-line treatments of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), cHL-NS2 is an independent indicator for worse PFS.
Adult ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Bleomycin/therapeutic use* ; Cyclophosphamide/therapeutic use* ; Dacarbazine/therapeutic use* ; Doxorubicin/therapeutic use* ; Etoposide/therapeutic use* ; Hodgkin Disease/drug therapy* ; Humans ; Necrosis/drug therapy* ; Prednisone/therapeutic use* ; Prognosis ; Retrospective Studies ; Sclerosis/drug therapy* ; Vinblastine/therapeutic use* ; Vincristine/therapeutic use*

A 40-year-old man presented with pruritic, multiple, variable-sized, erythematous umbilicated papules on the trunk and both extremities for 4 months. He was diagnosed with Hodgkin's lymphoma (stage IIA) after histopathologic examination of a neck mass that developed a month ago. A punch biopsy was performed on his right lower leg. Histological examination showed transepidermal elimination of the degenerated collagen. Masson's trichrome staining was performed to distinguish collagen fibers from the muscular tissue; using Masson's stain, the collagen appeared as a bluish color crossing from the dermis to the epidermis. The diagnosis of acquired reactive perforating collagenosis was made. The skin lesions showed much improvement after 6 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy. Acquired perforating disorders are a group of cutaneous disorders that occur in adults with chronic kidney disease or diabetes mellitus. Cases of acquired perforating disorders associated with Hodgkin's lymphoma have been rarely reported in the English literature. To our knowledge, this is the first case of acquired reactive perforating collagenosis in a Korean patient with Hodgkin's lymphoma.
Adult ; Biopsy ; Bleomycin ; Collagen ; Dacarbazine ; Dermis ; Diabetes Mellitus ; Diagnosis ; Doxorubicin ; Drug Therapy ; Epidermis ; Extremities ; Hodgkin Disease ; Humans ; Leg ; Neck ; Renal Insufficiency, Chronic ; Skin ; Vinblastine

Placental abruption is a condition that should be carefully considered in perinatal management because it is associated with serious events in both the mother and neonate, such as intrauterine fetal death, cerebral palsy, obstetric critical bleeding, and uncontrollable bleeding. The concomitant presence of disseminated intravascular coagulation (DIC) more easily causes critical bleeding that may necessitate hysterectomy or multi-organ failure resulting in maternal death. Therefore, early management should be provided to prevent progression to serious conditions by performing both hemostatic procedures and DIC treatment. To take measures to improve the outcomes in both the mother and neonate, health guidance for pregnant women, early diagnosis, early treatment, development of the emergency care system, and provision of a system for transport to higher-level medical institutions should be implemented.
Abruptio Placentae ; Cerebral Palsy ; Dacarbazine ; Disseminated Intravascular Coagulation ; Early Diagnosis ; Emergency Medical Services ; Female ; Fetal Death ; Fibrinogen ; Hemorrhage ; Humans ; Hysterectomy ; Infant, Newborn ; Maternal Death ; Mothers ; Obstetric Surgical Procedures ; Pregnancy ; Pregnant Women

Enteroviral infections are common in neonates. One important infection pathway is vertical transmission from an infected mother to her neonate. Here, we report the early detection and successful treatment of a vertically transmitted fulminant enteroviral infection associated with myocarditis and hepatitis. The patient had a sudden onset of high fever on the fourth day of life and developed severe, rapidly progressing symptoms of disseminated intravascular coagulopathy (DIC), hepatitis, and myocarditis accompanied by tachyarrhythmia. As it was the peak season for enteroviral infections and both the mother and the patient's 36-month-old sibling had a high fever around the time of delivery, we suspected an enteroviral infection. Thus, we initiated prompt evaluation of enteroviral infection, as well as close observation and intensive care of the neonate. We strongly recommend evaluation for the possibility of vertical enterovirus infection in neonates when the mother is suspected of having a viral infection (e.g., high fever and negative results from bacterial infectious studies) around the time of delivery and when the neonate shows some early symptoms of infectious diseases such as thrombocytopenia, DIC, hepatitis, and myocarditis. Early detection of enteroviral infections and prompt implementation of proper treatment are key to reduce the risk of complications and mortality associated with enteroviral infections in neonates.
Arrhythmias, Cardiac ; Child, Preschool ; Communicable Diseases ; Critical Care ; Dacarbazine ; Enterovirus ; Enterovirus Infections ; Fever ; Hepatitis ; Humans ; Infant, Newborn ; Mortality ; Mothers ; Myocarditis ; Seasons ; Siblings ; Tachycardia ; Thrombocytopenia

OBJECTIVES: In most countries around the world, sex work is an illegal activity. Female sex workers (FSWs) in Iran hide their identities, and they are known to be a hard-to-reach population. Despite free access to HIV testing, fewer than half of FSWs receive HIV testing. The purpose of this study was to characterize the reasons for which FSWs do not seek testing at drop-in centers (DICs) and voluntary counseling and testing (VCT) centers in Iran. METHODS: A qualitative study was conducted in 2016. The participants were 24 FSWs who received services at VCT centers and DICs for vulnerable females in the north of Iran and 9 males who were the clients of FSWs. In this study, we made use of purposive sampling and carried out a thematic analysis. RESULTS: We found 4 major and 6 minor themes. The major themes were: fear of being infected (with HIV), stigma, indifference, and knowledge. CONCLUSIONS: Despite the significant efforts made by the government of Iran to establish and expand DICs for vulnerable females, the number of FSWs receiving services at these centers has not been very considerable. Consequently, by introducing and implementing training programs for peer groups, it may be possible to take steps toward establishing strategic programs for the control and prevention of HIV/AIDS.
Counseling ; Dacarbazine ; Education ; Female* ; Health Services* ; HIV ; Humans ; Iran ; Male ; Peer Group ; Sex Workers*

OBJECTIVE: Clinically, consumptive coagulopathy, such as disseminated intravascular coagulopathy (DIC), is the most important among the common venomous snakebite complications owing to the serious hemorrhage risk associated with this condition. We evaluated the predictive value of the delta neutrophil index (DNI)—a new indicator for immature granulocytes—for DIC diagnosis. METHODS: This retrospective observational study consecutively assessed adult patients with venomous snakebites for over 51 months. Patients were categorized into the no DIC and DIC groups. DNI values were measured within 24 hours after snakebite. RESULTS: Thirty patients (26.3%) developed DIC. The DIC group had significantly higher median initial DNI than the no DIC group (0% vs. 0.2%, P < 0.001). When the DIC group was divided into early and late groups (within and over 24 hours after snakebite, respectively), the DNI of the former was significantly higher than that of the latter and no DIC group. The late DIC group had significantly higher DNI than the no DIC group. Furthermore, DNI positively correlated with the DIC score (r=0.548, P < 0.001). The initial DNI (odds ratio, 4.449; 95% confidence interval, 1.738 to 11.388; P=0.002) was an early DIC predictor. The area under the curve based on the initial DNI’s receiver operating characteristic curve was 0.724. CONCLUSION: DNI values were significantly higher in the DIC group. Additionally, DNI was an early predictor of DIC development in patients with venomous snakebites in the emergency department.
Adult ; Dacarbazine ; Diagnosis ; Emergency Service, Hospital ; Hemorrhage ; Humans ; Neutrophils* ; Observational Study ; Retrospective Studies ; ROC Curve ; Snake Bites* ; Venoms*

BACKGROUND/AIMS: Recently, recombinant human soluble thrombomodulin (rTM) has been developed as a new drug for disseminated intravascular coagulation (DIC). This study aims to evaluate the clinical benefit of rTM in patients with sepsis-induced DIC caused by acute cholangitis who underwent biliary drainage. METHODS: Patients were divided into two groups: the rTM therapy group and the non-rTM therapy group. The primary outcome was the DIC resolution rate at 7 days, and the secondary outcome was 28-day mortality rate. RESULTS: Thirty-five patients were treated by rTM, and 36 patients were treated without rTM for DIC. The rate of resolution of DIC at day 7 was significantly higher in the rTM group than in the non-rTM group (82.9% vs 55.6%, p=0.0012). Compared with the non-rTM group, the 28-day survival rate of the r-TM group was significantly higher (rTM vs non-rTM, 91.4% vs 69.4%, p=0.014). According to multivariate analysis, non-rTM (hazard ratio [HR], 2.681) and CRP (HR, 2.370) were factors related to decreased survival. CONCLUSIONS: rTM treatment may have a positive impact on improving DIC and survival rates in patients with severe acute cholangitis.
Cholangitis* ; Dacarbazine ; Disseminated Intravascular Coagulation* ; Drainage ; Humans ; Mortality ; Multivariate Analysis ; Survival Rate ; Thrombomodulin* ; Thrombosis