A genome-wide CRISPR screen reveals that antagonism of glutamine metabolism sensitizes head and neck squamous cell carcinoma to ferroptotic cell death.

Glutamine is a conditionally essential amino acid for the growth and survival of rapidly proliferating cancer cells. Many cancers are addicted to glutamine, and as a result, targeting glutamine metabolism has been explored clinically as a therapeutic approach. Glutamine-catalyzing enzymes are highly expressed in primary and metastatic head and neck squamous cell carcinoma (HNSCC). However, the nature of the glutamine-associated pathways in this aggressive cancer type has not been elucidated. Here, we explored the therapeutic potential of a broad glutamine antagonist, DRP-104 (sirpiglenastat), in HNSCC tumors and aimed at shedding light on glutamine-dependent pathways in this disease. We observed a potent antitumoral effect of sirpiglenastat in HPV- and HPV + HNSCC xenografts. We conducted a whole-genome CRISPR screen and metabolomics analyses to identify mechanisms of sensitivity and resistance to glutamine metabolism blockade. These approaches revealed that glutamine metabolism blockade results in the rapid buildup of polyunsaturated fatty acids (PUFAs) via autophagy nutrient-sensing pathways. Finally, our analysis demonstrated that GPX4 mediates the protection of HNSCC cells from accumulating toxic lipid peroxides; hence, glutamine blockade sensitizes HNSCC cells to ferroptosis cell death upon GPX4 inhibition. These findings demonstrate the therapeutic potential of sirpiglenastat in HNSCC and establish a novel link between glutamine metabolism and ferroptosis, which may be uniquely translated into targeted glutamine-ferroptosis combination therapies.

[Treatment status of tyrosine kinase inhibitor for newly-diagnosed chronic myeloid leukemia: a domestic multi-centre retrospective real-world study].

Objective: To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China. Methods: Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed. Results: 6 893 patients in CP (n=6 453, 93.6%) or AP (n=440, 6.4%) receiving initial imatinib (n=4 906, 71.2%), nilotinib (n=1 157, 16.8%), dasatinib (n=298, 4.3%) or flumatinib (n=532, 7.2%) -therapy. With the median follow-up of 43 (IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance (n=1 055, 15.3%), intolerance (n=248, 3.6%), pursuit of better efficacy (n=168, 2.4%), economic or other reasons (n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph(+) ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph(+) ACA, poorer TFS; Ph(+) ACA, poorer OS. Conclusion: At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Analysis of retromuscular drain output and postoperative outcomes for heavyweight versus mediumweight polypropylene mesh following open ventral hernia repair.

PURPOSE: Heavyweight polypropylene (HWPP) mesh is thought to increase inflammatory response and delay tissue integration compared to mediumweight (MWPP). Reactive fluid volume (i.e., drain output) may be a reasonable surrogate for integration. We hypothesized that daily drain output is higher with HWPP compared to MWPP in open retromuscular ventral hernia repair (VHR). METHODS: This is a post-hoc analysis of a multicenter, randomized clinical trial conducted March 2017-April 2019 comparing MWPP and HWPP for VHR. Retromuscular drain output in milliliters was measured at 24-h intervals up to postoperative day seven. Univariate analyses compared differences in daily drain output and time to drain removal. Multivariable analyses compared total drain output and wound morbidity within 30 days and hernia recurrence at 1 year. RESULTS: 288 patients were included; 140 (48.6%) HWPP and 148 (51.4%) MWPP. Daily drain output for days 1-3 was higher for HWPP vs. MWPP (total volume: 837.8 mL vs. 656.5 mL) (p < 0.001), but similar on days 4-7 (p > 0.05). Median drain removal time was 5 days for both groups. Total drain output was not predictive of 30-day wound morbidity (p > 0.05) or hernia recurrence at 1 year (OR 1, p = 0.29). CONCLUSION: While HWPP mesh initially had higher drain outputs, it rapidly returned to levels similar to MWPP by postoperative day three and there was no difference in clinical outcomes. We believe that drains placed around HWPP mesh can be managed similarly to MWPP mesh.

Outcomes of posterior component separation with transversus abdominis release for repair of abdominally based breast reconstruction donor site hernias.

PURPOSE: Abdominally based autologous breast reconstruction (ABABR) is common after mastectomy, but carries a risk of complex abdominal wall hernias. We report experience with posterior component separation (PCS) and transversus abdominis release (TAR) with permanent synthetic mesh repair of ABABR-related hernias. METHODS: Patients at Cleveland Clinic Foundation and Penn State Health were identified retrospectively. Outcomes included postoperative complications, hernia recurrence, and patient-reported outcomes (PROs): Hernia Recurrence Inventory, HerQLes Summary Score, Patient-Reported Outcome Measurement Information System (PROMIS) Pain Intensity 3a Survey, and the Decision Regret Scale (DRS). RESULTS: Forty patients underwent PCS/TAR repair of hernias resulting from pedicled (35%), free (5%), muscle-sparing TRAMs (15%), and DIEPs (28%) from August 2014 to March 2021. Following PCS, 30-day complications included superficial surgical site infection (13%), seroma (8%), and superficial wound breakdown (5%). Five patients (20%) developed clinical hernia recurrence. At a minimum of 1 year, 17 (63%) reported a bulge, 12 (44%) reported pain, median HerQLes Quality Of Life Scores improved from 33 to 63/100 (p value < 0.01), PROMIS 3a Pain Intensity Scores improved from 52 to 38 (p value < 0.05), and DRS scores were consistent with low regret (20/100). CONCLUSION: ABABR-related hernias are complex and technically challenging due to missing abdominal wall components and denervation injury. After repair with PCS/TAR, patients had high rates of recurrence and bulge, but reported improved quality of life and pain and low regret. Surgeons should set realistic expectations regarding postoperative bulge and risk of hernia recurrence.

Abdominal wall mass resections: single-center closure practices and outcomes following oncologic resections of abdominal wall fascia.

PURPOSE: Radical resections for abdominal wall tumors are rare, thus yielding limited data on reconstruction of defects. We describe surgical management and long-term outcomes following radical tumor resection. METHODS: This was a single-center retrospective review of patients between January 2010 and December 2022. Variables included operative characteristics, wound complications, hernia development, tumor recurrence, and reoperation. A multivariable analysis compared wound morbidity for suture and mesh repairs while adjusting for defect width, fascial closure, and CDC wound class. RESULTS: 120 patients were identified. Mean follow-up was 3.9 ± 3.4 years. Seventy-five (62.5%) of the masses were primary; most commonly desmoid (n = 25) and endometrioma (n = 27). Forty-five masses were metastases. Mean tumor width was 6.2 ± 3.4 cm; mean defect width was 8.1 ± 4.1 cm. Sixty-one patients (50.8%) had mesh placed, with variation in technique. Postoperative CT scans were available for 88 (73.3%) patients. Forty SSOs (33.3%), 11 SSIs (9.2%), and 18 (15%) SSOPIs occurred within 30 days. On multivariable analysis, increased defect width was associated with SSOPI (OR 1.17, p = 0.041) and CDC wound class II-III was associated with SSI (OR 8.38 and 49.1, p < 0.05) and SSOPI (OR 5.77 and 17.4, p < 0.05); mesh was not associated with these outcomes. Seven patients (5.8%) underwent 30-day reoperations and 35 (20.8%) required additional operations after 30 days. Thirteen percent developed abdominal wall (n = 8) or intra-abdominal tumor recurrence (n = 8) requiring reoperation. Twenty-seven (22.5%) patients developed hernias with a mean fascial defect width of 9.8 ± 7.2 cm. CONCLUSION: Abdominal wall mass resections are morbid, often contaminated cases with high postoperative complication rates. Risks and benefits of mesh implantation should be tailored on an individual basis.

[To compare the efficacy and incidence of severe hematological adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia].

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.

[Effect of recombinant human thrombin for hemostasis in liver resection: a randomized controlled phase â ¢ clinical trial].

Objective: To evaluate the hemostatic efficacy, safety and immunogenicity of recombinant human thrombin in the treatment of liver wounds that still ooze after conventional surgical hemostasis. Methods: A multicenter, stratified randomized, double-blind, placebo-controlled phase Ⅲ trial with a planned enrollment of 510 subjects at 33 centers, with a 2∶1 randomization to the thrombin group versus the placebo group. An interim analysis will be conducted after approximately 70% of the subjects have completed the observation period. The primary efficacy endpoint was the rate of hemostasis within 6 minutes at the point of bleeding that could be evaluated. Safety analysis was performed one month after surgery, and the positive rates of anti-drug antibody (ADA) and neutralizing antibody were evaluated. Results: At the interim analysis, a total of 348 subjects had been randomized and received the study drug (215 were male and 133 were female). They were aged 19-69 (52.9±10.9)years. Among them, 232 were in the thrombin group and 116 were in the placebo group, with balanced and comparable demographics and baseline characteristics between the two groups. The hemostasis rate at 6 minutes was 71.6% (95%CI:65.75%-77.36%) in the thrombin group and 44.0% (95%CI: 34.93%-53.00%) in the placebo group, respectively (P<0.001). No grade≥3 drug-related adverse events and no drug-related deaths were reported from the study.No recombinant human thrombin-induced immunologically-enhanced ADA or immunologically-induced ADA was detected after topical use in subjects. Conclusion: Recombinant human thrombin has shown significant hemostatic efficacy and good safety in controlling bleeding during liver resection surgery, while also demonstrating low immunogenicity characteristics.

Incisional hernia rates following midline laparotomy in the obese patient: a retrospective review.

PURPOSE: Incisional hernia is the most common complication of midline laparotomy. Although obesity is a known risk factor, the incidence of hernia formation in obese patients is not well defined. We sought to define the rate of incisional hernia formation in obese patients undergoing primary midline laparotomy in a large academic medical center. METHODS: Obese patients (BMI ≥ 30 kg/m2) who underwent an elective or urgent primary midline laparotomy from 2017 to 2021 at our institution were retrospectively identified. A blinded hernia surgeon reviewed imaging to assess for incisional hernia formation, defined as a midline fascial defect with intra-abdominal contents herniated outside of the peritoneal cavity. RESULTS: A total of 2241 patients met inclusion criteria. Cross-sectional imaging was available for 914 (41%) of these patients. The median BMI for all patients was 34.3 kg/m2 (range 30.0-59.1). Median time to follow-up imaging was 316 days (181-957, IQR = 185) for all patients and 316 days (201-903, IQR = 184) for patients with incisional hernia. In total, 474 (51.9%) had radiographic evidence of an incisional hernia. Colorectal and General Surgery demonstrated the highest rate of incisional hernia (p < 0.001). During the study period, 138 patients (15.1%) underwent surgical repair of their hernia at our institution, with the highest percentage being Colorectal Surgery patients. CONCLUSION: There is a high rate of hernia formation and subsequent hernia repair in obese patients undergoing midline laparotomy. Most importantly, these findings demonstrate an immediate and pressing need to identify the patient risk factors and technical issues related to this rate of hernia formation.

Opioid prescribing practices and patient-requested refill patterns following laparoscopic inguinal hernia repair.

PURPOSE: Excessive post-operative opioid prescribing has led to efforts to match prescriptions with patient need after surgery. We investigated opioid prescribing practices, rate of patient-requested opioid refills, and associated factors after laparoscopic inguinal hernia repair (LIHR). METHODS: LIHRs at a single institution from 3/2019 to 3/2021 were queried from the Abdominal Core Health Quality Collaborative for demographics, perioperative details, and patient-reported opioid usage. Opioid prescriptions at discharge and opioid refills were extracted from the medical record. Univariate and multivariable regression were used to identify factors associated with opioid refills within 30-days of surgery. RESULTS: Four hundred and ninety LIHR patients were analyzed. The median number of opioid tablets prescribed was 12 [interquartile range (IQR) 10-15], and 4% requested a refill. On univariate analysis, patients who requested refills were younger [55 years (IQR 37-61) vs. 62 years (IQR 36.8-61), p = 0.012], more likely to have undergone transabdominal preperitoneal repair (75% vs. 26.4%, p < 0.001), have a scrotal component (30% vs. 11%, p = 0.022), and have permanent tacks used (80% vs. 49.4%, p = 0.014). There was a 12% increase in the odds of opioid refill for every 1 tablet of oxycodone prescribed at discharge (95% CI for OR 1.04-1.21, p = 0.003) after controlling for age and surgery type. Patient-reported opioid use was available for 289 (59%) patients. Post-operatively, 67% of patients used ≤ 4 opioid tablets, and 87% used no more than 10 opioid tablets. CONCLUSION: Most patients use fewer opioid tablets than prescribed. Requests for opioid refills are rare following LIHR (4%) and associated with higher opioid prescribing.

Ileus rate after abdominal wall reconstruction: a retrospective analysis of two clinical trials.

PURPOSE: Postoperative ileus (POI) is the paralytic disruption of gastrointestinal motility, a common complication following abdominal wall reconstruction that often leads to increased patient morbidity and length of stay (LOS). We reviewed two randomized clinical trials to determine POI rates, predictive factors, LOS, and associated cost. METHODS: Two randomized trials were performed from 2017-2019 with all patients receiving elective open abdominal wall reconstruction with retromuscular mesh. Using multivariate logistic regression, we performed a retrospective analysis including demographics and operative details from patients at a single site to determine predictive factors for POI. All medical costs encompassing surgery and the 30-day postoperative period were compared between ileus and non-ileus groups. RESULTS: Four hundred and seventy patients were reviewed with a POI rate of 13.0% (N = 61). There were no differences in age, body mass index (BMI), history of abdominal surgery, or comorbidities between patients with and without POI. Logistic regression showed no association with POI and age, BMI, hernia width, or operative time lasting longer than 4 h. Median LOS was 8 days for patients with POI compared to five for those without (p < 0.001). Relative median 30-day costs were 1.19 in patients with ileus and 1.0 in those without (p < 0.001). CONCLUSION: We identified a 13% rate of POI in patients undergoing open abdominal wall reconstruction with mesh with no clearly identified predisposing factors. This resulted in a 3 days increase in median LOS and 19% additional costs. Further efforts should be devoted to investigating interventions that may reduce postoperative ileus after abdominal wall reconstruction.

Machine Learning in the Development of Adsorbents for Clean Energy Application and Greenhouse Gas Capture.

Addressing climate change challenges by reducing greenhouse gas levels requires innovative adsorbent materials for clean energy applications. Recent progress in machine learning has stimulated technological breakthroughs in the discovery, design, and deployment of materials with potential for high-performance and low-cost clean energy applications. This review summarizes basic machine learning methods-data collection, featurization, model generation, and model evaluation-and reviews their use in the development of robust adsorbent materials. Key case studies are provided where these methods are used to accelerate adsorbent materials design and discovery, optimize synthesis conditions, and understand complex feature-property relationships. The review provides a concise resource for researchers wishing to use machine learning methods to rapidly develop effective adsorbent materials with a positive impact on the environment.

Comparing anterior gastropexy to no anterior gastropexy for paraesophageal hernia repair: a study protocol for a randomized control trial.

BACKGROUND: More than half of patients undergoing paraesophageal hernia repair (PEHR) will have radiographic hernia recurrence at 5 years after surgery. Gastropexy is a relatively low-risk intervention that may decrease recurrence rates, but it has not been studied in a prospective manner. Our study aims to evaluate the effect of anterior gastropexy on recurrence rates after PEHR, compared to no anterior gastropexy. METHODS: This is a two-armed, single-blinded, registry-based, randomized controlled trial comparing anterior gastropexy to no anterior gastropexy in PEHR. Adult patients (≥18 years) with a symptomatic paraesophageal hernia measuring at least 5 cm in height on computed tomography, upper gastrointestinal series, or endoscopy undergoing elective minimally invasive repair are eligible for recruitment. Patients will be blinded to their arm of the trial. All patients will undergo laparoscopic or robotic PEHR, where some operative techniques (crural closure techniques and fundoplication use or avoidance) are left to the discretion of the operating surgeon. During the operation, after closure of the diaphragmatic crura, participants are randomized to receive either no anterior gastropexy (control arm) or anterior gastropexy (treatment arm). Two hundred forty participants will be recruited and followed for 1 year after surgery. The primary outcome is radiographic PEH recurrence at 1 year. Secondary outcomes are symptoms of gastroesophageal reflux disease, dysphagia, odynophagia, gas bloat, regurgitation, chest pain, abdominal pain, nausea, vomiting, postprandial pain, cardiovascular, and pulmonary symptoms as well as patient satisfaction in the immediate postoperative period and at 1-year follow-up. Outcome assessors will be blinded to the patients' intervention. DISCUSSION: This randomized controlled trial will examine the effect of anterior gastropexy on radiographic PEH recurrence and patient-reported outcomes. Anterior gastropexy has a theoretical benefit of decreasing PEH recurrence; however, this has not been proven beyond a suggestion of effectiveness in retrospective series. If anterior gastropexy reduces recurrence rates, it would likely become a routine component of surgical PEH management. If it does not reduce PEH recurrence, it will likely be abandoned. TRIAL REGISTRATION: ClinicalTrials.gov NCT04007952 . Registered on July 5, 2019.

[Long-term observation of the effect of atlantoaxial fusion on the growth and development of children's cervical spine].

Objective: To explore the effect of atlantoaxial fusion on the growth and development of children's cervical spine. Methods: The clinical data of 12 children with atlantoaxial dislocation who underwent posterior atlantoaxial fusion at Department of Orthopaedics,the 909th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army from June 2002 to September 2013 were retrospective analyzed. There were 7 males and 5 females,with age of (8.1±3.1)years (range:3 to 13 years).Nine cases were traumatic and 3 cases were congenital malformations,1 of the children had Down syndrome. All children underwent posterior atlantoaxial fusion. Furthermore,the information of the height and anteroposterior width of the cervical vertebral bodies and vertical growth rate of the fusion mass were collected from all patients immediately postoperatively and during the follow-up.The range of motion in cervical spine were collected preoperatively and during follow-up period. Data were compared using independent sample t test, paired sample t test and repeated-measurement. Results: All 12 children had regular follow-up within (122.4±25.3)months(range:65 to 163 months). The height and anteroposterior width of the cervical vertebral bodies were similar to these results with those in published reports of growth in normal children of the same age(all P<0.01). At the last follow-up,atlantoaxial fusion of 11 cases had substantial growth (vertical growth rate of the fusion mass:11 cases ≥10%, 1 case <10%);the range of motion in cervical spine was close to the normal level (flexion(55.2±5.0)°,extension (65.3±4.9)°,left bending (41.7±4.5)°,right bending (42.4±4.4)°,left rotation (66.4±5.6)°,right rotation (68.5±5.8)°). Conclusions: Atlantoaxial fusion surgery is satisfactory in the treatment of pediatric atlantoaxial dislocation.During the follow-up,the growth and development of the cervical spine is close to that of normal children of the same age.In long-term observation,it has been found that the operation has no negative effect on the growth and development of the children's cervical spine.

[Effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of patients with acute coronary syndrome undergoing percutaneous coronary intervention].

Objective: To investigate the effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of acute coronary syndrome(ACS) patients undergoing percutaneous coronary intervention(PCI). Methods: This study was a retrospective cohort study. ACS patients who underwent PCI in Beijing Anzhen Hospital from October 2015 to January 2017 were recruited. The inhibition rate of adenosine diphosphate(ADP) was monitored by thromboelastography. All of these patients were divided into clopidogrel resistance and non-resistance group according to the monitoring results. CYP2C19 genotype was detected by TaqMan probe-based real-time quantitative PCR. Patients were divided into slow, medium and fast metabolic group, according to the CYP2C19 genotype. After 12 months of follow-up, the end points included all-cause death, cardiac death, angina, myocardial infarction, stent thrombosis, ischemic stroke and hemorrhage were collected. Combined thrombotic events were defined as a composite of angina, myocardial infarction, stent thrombosis and ischemic stroke. The differences of the incidence of clinical events between groups were compared. Cox regression was used to analyze the effects of clopidogrel resistance and CYP2C19 genotype on the combined thrombotic events, cardiac death and hemorrhage. Results: A total of 1 696 patients were included, and the age was (59.4±9.6) years, with 1 280(75.5%) males. There were 471 cases(27.8%) in clopidogrel resistance group, and 1 225 cases(72.2%) in clopidogrel non-resistance group. There were 218 patients(12.9%) were in slow metabolic group, 668(39.4%) in medium metabolic group, and 810 (47.8%) in fast metabolic group. The median follow-up time was 13.3 months, and 131 cases were lost to follow-up, with a loss follow-up rate of 7.7%. Compared with the clopidogrel non-resistance group, the clopidogrel resistance group had a higher incidence of myocardial infarction(7.6%(36/471) vs. 5.1%(62/1 225), P=0.041), a lower incidence of hemorrhage (13.2%(62/471) vs. 17.9%(219/1 225), P=0.020) and minor hemorrhage(11.5%(54/471) vs. 15.8% (194/1 225), P=0.022). There were no statistically significant difference in all-cause death, cardiac death, angina, stent thrombosis, ischemic stroke and severe bleeding between clopidogrel resistance and non-resistance group(all P>0.05). There was no statistically significant difference in the incidence of endpoint events among different CYP2C19 genotypes (all P>0.05). Cox regression analysis showed that clopidogrel resistance was an independent factor of combined thrombotic events (OR=2.334, 95%CI 1.215-4.443, P=0.016) and bleeding events (OR=0.481, 95%CI 0.174-0.901, P=0.023). While CYP2C19 genotype was not independent factor for combined thrombotic events, cardiac death and hemorrhage (all P>0.05). Conclusion: For ACS patients after PCI, clopidogrel resistance can increase the risk of combined thrombotic events, but also reduce the risk of bleeding; while CYP2C19 genotype is not an independent factor for clinical prognosis.

DNAJA4 deficiency augments hyperthermia-induced Clusterin and ERK activation: two critical protective factors of human keratinocytes from hyperthermia-induced injury.

BACKGROUND: Hyperthermia upregulates DNAJA4, a member of heat shock proteins (HSPs) 40 family, in human keratinocytes and HPV-infected tissue. DNAJA4 deficiency enhances growth arrest induced by hyperthermia. Clusterin (CLU) and phosphorylated ERK (p-ERK) play a role in regulating cell proliferation and apoptosis, under environmental stress. OBJECTIVES: To examine the downstream molecules and signalling pathways of DNAJA4 and assess their roles in cell cycle and apoptosis of keratinocytes in response to hyperthermia. METHODS: Wild-type and DNAJA4-knockout (KO) HaCaT cells were exposed to either 44 °C (hyperthermia) or 37 °C (control) for 30 min. The expression levels of CLU and p-ERK were determined by RT-PCR and Western blotting. RNAi and PD98059 were used to inhibit the expression of CLU and p-ERK, respectively. Cell viability, cell cycle and apoptosis were analysed by MTS assay and flow cytometry. Fresh biopsy samples of human normal foreskin or condyloma acuminatum (CA) were utilized to examine the expression of CLU and p-ERK after ex vivo culture at 44 °C. RESULTS: The expression of CLU and p-ERK was significantly increased by hyperthermia treatment at 44 °C in HaCaT cells, foreskin and HPV-infected tissues. In HaCaT cells subjected to hyperthermia, DNAJA4 deficiency further augmented the expression of CLU and p-ERK. CLU deficiency enhanced the p-ERK expression. Hyperthermia-induced CLU and p-ERK exerted protective roles mainly through inhibiting apoptosis and maintaining cell cycle, respectively. CONCLUSIONS: In keratinocytes, CLU and p-ERK are induced by hyperthermia, an effect which can be further enhanced by DNAJA4 deficiency. CLU deficiency also increases p-ERK expression. Both CLU and p-ERK are critical protective factors of human keratinocytes from hyperthermia-induced injury.

[Diagnostic value of endoscopic ultrasonography, fibroscan, acoustic radiation pulse imaging, serological index, and their combination for early stage liver cirrhosis].

Objective: To investigate the diagnostic value of endoscopic ultrasonography (EUS), Fibroscan, acoustic radiation force impulse (ARFI), and aspartate aminotransferase-to-platelet ratio (APRI) and their combination for early stage liver cirrhosis. Methods: Three hundred and twenty-two hospitalized patients who had been diagnosed with chronic viral liver disease from March 2016 to April 2018 were included. According to the clinical diagnosis, patients were divided into chronic hepatitis and the early stage liver cirrhosis group (Child-Pugh A grade). All patients were examined by Fibroscan to detect liver stiffness measurement (LSM), ARFI to detect liver virtual touch tissue quantification (VTQ) value, esophagogastroduodenoscopy and EUS to detect esophagogastric varices, laboratory and imaging examination. The index of EUS, Fibroscan, ARFI, and APRI was analyzed and the regression model was established by binary logistic regression, and the diagnostic efficacy of the above index and regression model for early stage of cirrhosis was evaluated by the area under a receiver operating characteristic curve (AUROCs). Results: An early stage cirrhosis group had significantly higher detection rate with EUS (esophagogastric varices), Fibroscan (LSM), ARFI (VTQ) and APRI than chronic hepatitis group [76.7% vs. 10.7%, 10.4 (7.8, 17.3) vs. 6.1 (5.2, 8.4) kPa, 1.71(1.48, 2.07) m/s vs. 1.25(1.14, 1.43) m/s and 0.65 (0.38, 1.15) vs. 0.38(0.26, 0.62), respectively]. The corresponding chi-square test were 140.86, Z = -9.069, Z = -9.948 and Z = -5.764, respectively and the differences were statistically significant (P < 0.01). The areas under the receiver operating characteristic curve and regression model were 0.830 (0.783 ~ 0.877), 0.793 (0.744 ~ 0.841), 0.821 (0.775 ~ 0.868), 0.686 (0.628 ~ 0.744) and 0.947 (0.925 ~ 0.969) for the diagnosis of early stage cirrhosis, respectively. Among them, the regression model of three indices (EUS, LSM and VTQ) had the largest AUROCs (0.947) and the corresponding sensitivity and specificity were 0.878 and 0.867, respectively. Conclusion: The combination of EUS, LSM and ARFI had a superior diagnostic value for early stage liver cirrhosis, and may improve the diagnosis rate and reduce the misdiagnosis rate.

Telescopic dissection versus balloon dissection for laparoscopic totally extraperitoneal inguinal hernia repair (TEP): a registry-based randomized controlled trial.

OBJECTIVE: Laparoscopic totally extraperitoneal inguinal hernia repair (TEP) can be performed using either telescopic (TD) or balloon dissection (BD). The use of a disposable balloon dissector increases the cost of TEP. However, it remains unclear whether BD saves enough time to justify its cost. We hypothesized that BD would consistently save 15 min in operative time. To test this hypothesis, we designed a registry-based randomized controlled trial (RB-RCT) embedded into the Americas Hernia Society Quality Collaborative. METHODS: A single-blinded, parallel, RB-RCT was conducted. Adults with inguinal hernias presenting for elective repair were screened. Patients with unilateral hernias deemed fit to undergo TEP were eligible; those with bilateral hernias (BIH) or undergoing open repair were excluded. Individuals were randomized to TD or BD with a disposable device. TEP was performed with synthetic mesh and tacks. Subjects were blinded and followed up for 30 day. Main outcome was operative time. RESULTS: 207 patients were screened: 166 were excluded and 41 were randomized (21 BD, 20 TD). One patient (TD group) was excluded due to the incidental finding of BIH. 40 patients were analyzed (median age 56, median BMI 26 kg/m2, 98% males). Hernias were 72% indirect, 17% direct, 10% pantaloon, and 8% recurrent. Other than obesity (26.5% vs. 0, p = 0.018), there were no baseline differences between the groups. Median operative times were similar (TD 43 min, IQR 33-63; BD 46 min, IQR 35-90, p = 0.490). There were 2 seromas and 2 hematomas in the BD group, and none in the TD (p = 0.108). CONCLUSIONS: BD does not consistently result in 15-min time saving during TEP. Use of a disposable balloon dissector can be deferred in the experienced hands. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03276871).

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) promotes EGF receptor signaling of oral squamous cell carcinoma metastasis via the complex N-glycosylation.

Aberrant protein glycosylation could be a distinct surface-marker of cancer cells that influences cancer progression and metastasis because glycosylation can regulate membrane protein folding which alters receptor activation and changes epitope exposure for antibody (Ab) recognition. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a glycophosphoinositol-anchored protein, is a heavily glycosylated tumor antigen. However, the clinical significance and biological effect of CEACAM6 glycosylation has not been addressed in cancers. We recently developed an anti-CEACAM6 Ab (TMU) from an immune llama library which can be engineered to a single-domain (sd)Ab or a heavy-chain (HC)Ab. The TMU HCAb specifically recognized glycosylated CEACAM6 compared to the conventional antibodies. Using the TMU HCAb, we found that glycosylated CEACAM6 was a tumor marker associated with recurrence in early-stage OSCC (oral squamous cell carcinoma) patients. CEACAM6 promoted OSCC cell invasion, migration, cytoskeletal rearrangement, and metastasis via interaction with epidermal growth factor (EGF) receptor (EGFR) and enhancing EGFR activation, clustering and intracellular signaling cascades. These functions were modulated by N-acetylglucosaminyltransferase 5 (MGAT5) which mediated N-glycosylation at Asn256 (N256) of CEACAM6. Finally, the TMU sdAb and HCAb treatment inhibited the migration, invasion and EGF-induced signaling in CEACAM6-overexpressing cells. In conclusion, the complex N-glycosylation of CEACAM6 is critical for EGFR signaling of OSCC invasion and metastasis. Targeting glycosylated CEACAM6 with the TMU sdAb or TMU HCAb could be a feasible therapy for OSCC.

Is there an association between surgeon hat type and 30-day wound events following ventral hernia repair?

INTRODUCTION: While several patient and operative variables have been shown to be associated with an increased risk of postoperative wound events, the association between surgical hat type worn by surgeons and postoperative wound events remains controversial. The purpose of this study is to investigate the association between type of surgical hat worn by surgeons and the incidence of postoperative wound events following ventral hernia repair using the Americas Hernia Society Quality Collaborative database. METHODS: All surgeons who input at least ten patients with 30-day follow-up into the AHSQC were identified. These surgeons were sent a survey asking them to identify the type of surgical hat they wear in the operating room. The association of the type of surgical hat worn, patient variables, and operative factors with 30-day wound events was investigated using multivariate logistic regression. RESULTS: A total of 68 surgeons responded to the survey, resulting in 6210 cases available for analysis. The type of surgical hat worn by surgeons was not found to be associated with an increased risk of 30-day surgical site infections or surgical site occurrences requiring procedural intervention. CONCLUSION: Our study is the first study to directly compare the association of surgical hat type with postoperative wound events. There is no association between the type of surgical hat worn and the incidence of postoperative wound events following ventral hernia repair. Our findings suggest that surgical hate type may be chosen at the discretion of operating room personnel without fear of detriment to their patients.