Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma.

AIMS: Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. METHODS: Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. RESULTS: SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1ß inhibition. CONCLUSIONS: SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.

The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism.

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

Clinical Significance of Combining Preoperative and Postoperative Albumin-Bilirubin Score in Colorectal Cancer.

PURPOSE: Albumin-bilirubin (ALBI) score is a well-known prognostic factor for various diseases, including colorectal cancer (CRC). However, little is known about the significance of postoperative ALBI score changes in patients with CRC. MATERIALS AND METHODS: A total of 723 patients who underwent surgery were enrolled. Preoperative ALBI (ALBI-pre) and postoperative ALBI (ALBI-post) scores were divided into low and high score groups. ALBI-trend was defined as a combination of four groups comprising the low and high ALBI-pre and ALBI-post score groups. Kaplan-Meier survival curves were used to compare the overall survival (OS) between the different ALBI groups. The Cox proportional hazards model was used to examine the independent relevant factors of OS. Stratification performance was compared between the different ALBI groupings using Harrell's concordance index (C-index). RESULTS: ALBI-pre, ALBI-post, and ALBI-trend score groups were significant prognostic factors of OS in the univariable analysis. However, multivariable analysis showed that ALBI-trend was an independent prognostic factor while ALBI-pre and ALBI-post were not. The C-index of ALBI-trend (0.622; 95% confidence interval [CI], 0.587 to 0.655) was higher than that of ALBI-pre (0.589; 95% CI, 0.557 to 0.621; bootstrap mean difference, 0.033; 95% CI, 0.013 to 0.057) and ALBI-post (0.575; 95% CI, 0.545 to 0.605; bootstrap mean difference, 0.047; 95% CI, 0.024 to 0.074). CONCLUSION: Combining ALBI-pre and ALBI-post scores is an independent prognostic factor of OS and shows superior predictive power compared to ALBI-pre or ALBI-post alone in patients with CRC.

Sequence preference and structural heterogeneity of BZ junctions.

BZ junctions, which connect B-DNA to Z-DNA, are necessary for local transformation of B-DNA to Z-DNA in the genome. However, the limited information on the junction-forming sequences and junction structures has led to a lack of understanding of the structural diversity and sequence preferences of BZ junctions. We determined three crystal structures of BZ junctions with diverse sequences followed by spectroscopic validation of DNA conformation. The structural features of the BZ junctions were well conserved regardless of sequences via the continuous base stacking through B-to-Z DNA with A-T base extrusion. However, the sequence-dependent structural heterogeneity of the junctions was also observed in base step parameters that are correlated with steric constraints imposed during Z-DNA formation. Further, circular dichroism and fluorescence-based analysis of BZ junctions revealed that a base extrusion was only found at the A-T base pair present next to a stable dinucleotide Z-DNA unit. Our findings suggest that Z-DNA formation in the genome is influenced by the sequence preference for BZ junctions.

A Case of Juvenile Psammomatoid Ossifying Fibroma on Skull Base.

Juvenile psammomatoid ossifying fibroma (JPOF) is a rare tumor that occurs in maxillary sinus or orbit. Complete removal is required due to the aggressive and locally destructive nature. It is hard to distinguish from psammomatoid meningioma in cranial lesion and to remove completely. The authors are presenting a case of 26-year-old male with JPOF on skull base and report this case with review of literature.

Surgical Outcomes of Bony Batten Grafting to Correct Caudal Septal Deviation in Septoplasty.

IMPROTANCE: Correction of caudal septal deviation with a batten graft has been popularized recently. However, few reports have documented the surgical outcomes of this technique, especially the use of bony batten grafts in septoplasty. OBJECTIVE: To evaluate the surgical outcomes of bony batten grafting for the management of caudal septal deviation in endonasal septoplasty. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study evaluates the medical records of 141 patients with caudal septal deviation who underwent septoplasty using bony batten grafts from September 1, 2011, through February 29, 2016, at a tertiary referral hospital. Patients were divided into primary and secondary surgery groups. Patients were also divided into the septoplasty plus turbinate surgery and the septoplasty only group. Endoscopic assessment of deviation correction was performed, and postoperative complications were analyzed. MAIN OUTCOMES AND MEASURES: Patient satisfaction and symptom improvement were evaluated via telephone interviews by using the Nasal Obstruction Symptoms Evaluation (NOSE) scores. RESULTS: Of the 141 patients (24 women [17%] and 117 men [83%]; mean [SD] age, 32.8 [12.9] years), 86 (61%) rated their symptoms in the postoperative survey as much improved; 50 (35.5%), improved; 4 (2.8%), no change; and 1 (0.7%), worse. All patients had significantly improved mean (SD) postoperative NOSE scores (28.7 [22.0]; 95% CI, 25.0-32.4) compared with preoperative scores (70.5 [26.7]; 95% CI, 66.0-75.0; P < .001). No significant intergroup differences were observed in surgical outcome between the 116 patients undergoing primary surgery (mean [SD] NOSE score, 28.2 [21.9]) and 25 undergoing secondary surgery (mean [SD] NOSE score, 30.8 [24.3]; P = .34). No significant difference in surgical outcome was found between the 102 patients in the turbinate surgery group (mean [SD] NOSE score, 28.1 [20.8]) and 39 in the septoplasty only group (mean [SD] NOSE score, 30.4 [23.7]; P = .65). On endoscopic examination for surgical outcome, 128 patients (90.8%) had a straight septum and 13 (9.2%) had improved but residual caudal deviation. Postoperative complications included septal hematoma in 4 patients, hyposmia in 2, and chondritis in 1; all patients were treated successfully. Four patients required revision surgery because of incomplete functional correction or a desire for rhinoplasty. CONCLUSIONS AND RELEVANCE: Septoplasty using bony batten grafts is useful for correcting caudal septal deviation with favorable surgical outcomes and an acceptable complication rate. LEVEL OF EVIDENCE: 3.

New strategy of closed suction drainage after primary total hip arthroplasty.

OBJECTIVE: The purpose of this study was to evaluate the effect of late applied negative pressure on postoperative drain output after primary total hip arthroplasty (THA). PATIENTS AND METHODS: 100 patients (100 hips) were treated by closed suction drainage applying negative pressure immediately after THA (group I). The remaining 100 patients (100 hips) were treated by the same drainage system, but the negative pressure was not applied in the first 24 h after THA and then negative pressure was applied (group II). RESULTS: The mean total drain output was different between the two groups (group I: 597 ± 200.1 mL, group II: 403 ± 204.1 mL; p < 0.05). Reported drain output from immediate postoperative to postoperative day one was 369 ± 125.5 ml in group I and 221 ± 141.3 ml in group II (p < 0.05). The change of hemoglobin from immediate postoperative to 24 h after THA was lower in group II (group I: 1.5 ± 0.62 g/dL, group II: 1.1 ± 0.73 g/dL; p = 0.004). The mean unit number of blood transfusions was 1.0 (range, 0.0-5.0) in group I and 0.3 (range, 0.0-2.0) in group II (p < 0.05). There was no difference in Harris hip score between the two groups at postoperative 1 year or last follow-up (p = 0.073). CONCLUSION: The minor change in drain system management can reduce postoperative blood loss after primary THA and the need for transfusion. LEVEL OF EVIDENCE: Level III, Therapeutic study.

Treatment Strategy for Revision Rhinoplasty in Asians.

Revision rhinoplasty in Asian patients is associated with problems related to the use of grafts or implant materials. Moreover, the septal cartilage of Asian individuals is generally weak and small, which makes it particularly vulnerable to injury or secondary deformity during primary surgery. Hence, there is an increased demand for major reconstruction of the septal cartilage framework during revision surgery in Asian patients. In revision rhinoplasty of the nose in Asian patients, appropriate management of the graft or implant is vital. The common problems resulting in the need for revision surgery include displacement, malposition, extrusion, recurrent inflammation, and infection of dorsally implanted alloplastic material. A short-nose deformity following silicone rhinoplasty is also a common problem that is difficult to manage. Furthermore, residual or recurrent deviation of the deviated nose, undercorrection of the convex nasal dorsum, and tip graft-related complications are frequently encountered problems that require revision. In revision rhinoplasty for Asian patients, autologous tissues, such as conchal cartilage and costal cartilage, play a pivotal role for use as a new dorsal implant or building block for major septal reconstruction. Therefore, it is imperative for surgeons to familiarize themselves with the appropriate use of autologous tissues, particularly costal cartilage.

Results of Total Hip Arthroplasty after Core Decompression with Tantalum Rod for Osteonecrosis of the Femoral Head.

BACKGROUND: Early stage osteonecrosis of the femoral head (ONFH) has many treatment options including core decompression with implantation of a tantalum rod. The purpose of this study was to evaluate clinical and radiological outcomes and potential complications during conversion total hip arthroplasty (THA) in such patients. METHODS: Six male patients (8 hips) underwent THA subsequent to removing a tantalum rod (group I) from April 2010 to November 2011. We retrospectively reviewed the medical records of these patients. We enrolled 12 age- and sex-matched patients (16 hips) during the same period, who had undergone primary THA without a previous operation as the control group (group II). All patients were followed for at least 3 years. We checked the Harris hip score (HHS), operative time, and volume of blood loss. Radiological results, including inclination, anteversion of the acetabular cup, presence of periprosthetic osteolysis, and subsidence of femoral stem were checked at the last follow-up. RESULTS: The mean preoperative HHS values were 56.5 (range, 50 to 62) and 59.1 (range, 42 to 70) in groups I and II, respectively. The HHS improved to 96.0 (range, 93 to 100) and 97.6 (range, 93 to 100), respectively, at the 3-year follow-up (p = 0.172). Mean operation time was 98.8 minutes (range, 70 to 120 minutes) in group I and 77.5 minutes (range, 60 to 115 minutes) in group II (p = 0.006). Total blood loss volumes were 1,193.8 mL (range, 960 to 1,360 mL) and 944.1 mL (range, 640 to 1,280 mL) in groups I and II, respectively (p = 0.004). No significant differences in inclination or anteversion of acetabular cup and no evidence of osteolysis or subsidence of the femoral stem were reported in either group in radiological follow-up results. However, one case of squeaking occurred in group I during the follow-up. CONCLUSIONS: The two groups showed no clinical or radiological differences except extended operative time and increased blood loss. However, the incidence of squeaking (1 of 8 hips) was higher, as compared to the control group or previously reported values.

Multiple primary cancers involving lung cancer at a single tertiary hospital: Clinical features and prognosis.

BACKGROUND: The development of other primary cancers in patients with lung cancer is unfortunate and uncommon, although the frequency is increasing. The aim of this study was to determine the clinical features and prognosis in patients with multiple primary cancers (MPC) involving lung cancer. METHODS: After a retrospective review of 1644 patients who were newly diagnosed with primary lung cancer between 1998 and August 2012 at a tertiary hospital, 105 patients were included. RESULTS: The median age at the time of lung cancer diagnosis was 67 years, and 68 patients were male. Synchronous primary cancers occurred in 47% of the study population (49/105). Among those with metachronous cancer (56/105), the median interval between the diagnosis of lung cancer and another malignancy was 47.1 months; 21 patients were diagnosed with lung cancer as the first primary tumor. The most frequent type of other malignancy was urogenital (30%), followed by gastrointestinal (30%) and thyroid malignancies (16%). Advanced stage of lung cancer (hazard ratio (HR), 3.2; 95% confidence interval (CI), 1.8-5.7; P < 0.001), supportive care only as treatment for lung cancer (HR, 2.8; 95% CI, 1.3-6.0; P = 0.006), and head and neck cancer as another malignancy (HR, 3.9; 95% CI, 1.4-10.8; P = 0.010) were independent predictors of shorter survival from the time of diagnosis of the second primary cancer. CONCLUSION: Advanced lung cancer stage, symptomatic supportive care only without antitumor therapy for lung cancer, and head and neck cancer as another primary malignancy were poor prognostic factors in patients with MPC involving primary lung cancer.

Partial Superficial Parotidectomy via Retroauricular Hairline Incision.

OBJECTIVES: The purpose of this study was to evaluate the usefulness of retroauricular hair line incision (RAHI) in partial superficial parotidectomy by comparison with modified Blair incision or facelift incision. METHODS: Medical records of 73 patients with benign parotid tumor who underwent partial superficial parotidectomy were retrospectively reviewed. Size and location of tumors, operative time, occurrence of facial nerve paralysis and Frey's syndrome, and cosmetic outcomes were compared among RAHI, facelift incision (FLI), modified Blair incision (MBI) groups. RESULTS: RAHI group showed better cosmetic results than FLI group or MBI group compared with other type of incisions (P<0.001, P<0.001, respectively). Among the 3 groups, there were no significant differences of operative time and location of tumor (P=0.377), size of tumor (P>0.999), occurrence of temporary or permanent facial nerve paralysis (P=0.745) and Frey's syndrome (P=0.940). CONCLUSION: Partial superficial parotidectomy can be done safely by RAHI in most cases of benign parotid tumor. Compared with MBI or FLI, RAHI has better cosmetic outcome with no increase of operative time or postoperative complications.

Distinct Rayleigh scattering from hot spot mutant p53 proteins reveals cancer cells.

The scattering of light redirects and resonances when an electromagnetic wave interacts with electrons orbits in the hot spot core protein and oscillated electron of the gold nanoparticles (AuNP). This report demonstrates convincingly that resonant Rayleigh scattering generated from hot spot mutant p53 proteins is correspondence to cancer cells. Hot spot mutants have unique local electron density changes that affect specificity of DNA binding affinity compared with wild types. Rayleigh scattering changes introduced by hot-spot mutations were monitored by localized surface plasmon resonance (LSPR) shift changes. The LSPR λmax shift for hot-spot mutants ranged from 1.7 to 4.2 nm for mouse samples and from 0.64 nm to 2.66 nm for human samples, compared to 9.6 nm and 15 nm for wild type and mouse and human proteins, respectively with a detection sensitivity of p53 concentration at 17.9 nM. It is interesting that hot-spot mutants, which affect only interaction with DNA, launches affinitive changes as considerable as wild types. These changes propose that hot-spot mutants p53 proteins can be easily detected by local electron density alterations that disturbs the specificity of DNA binding of p53 core domain on the surface of the DNA probed-nanoplasmonic sensor.

Risk factors and survival outcomes for patients with anastomotic leakage after surgery for head and neck squamous cell carcinoma.

OBJECTIVES: This study evaluated the risk factors for anastomotic leakage (AL) and survival outcomes in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Patients with HNSCC who underwent surgery carrying potential AL from 2003 through 2009 were included in this study. Univariate and multivariate analyses were performed and patient survival was calculated by the Kaplan-Meier method. RESULTS: Of 232 eligible patients, 25 (10.8%) developed AL. Univariate analyses revealed that primary tumor site, salvage surgery, perineural invasion, radiotherapy, chemotherapy, and blood transfusion were significantly associated with the occurrence of AL (P<0.05). Independent risk factors for AL were salvage surgery and blood transfusion (P<0.01). On univariate analysis, AL was significantly associated with overall (OS) and disease-free survivals (DFS; P<0.05) but not with decreased locoregional control (LRC) rate (P=0.07). The 5-year DFS rate was significantly different between the non-leakage and leakage groups (70.9% vs. 27.7%, P<0.001). Multivariate analysis showed, however, that AL was not an independent variable of LRC, DFS, or OS (P>0.1). CONCLUSION: Patients who received salvage surgery and blood transfusion may require careful surveillance for development of AL, which has a tendency toward decreased survival.

Outcomes after endonasal septoplasty using caudal septal batten grafting.

BACKGROUND: This study evaluated surgical outcomes after endonasal septoplasty using caudal septal batten grafting for caudal septal deviation. METHODS: Fifty-six patients completed questionnaires to assess nasal obstruction by telephone interviews 8-63 months postoperatively (12.2 months on the average). In addition, patients assessed the severity of nasal symptoms (i.e., mouth breathing, mouth dryness, hyposmia, rhinorrhea, epistaxis, trouble sleeping, snoring, and being concerned about nasal problems) preoperatively and postoperatively using a visual analog scale (VAS). These VAS scores were compared with those of patients who underwent endonasal septoplasty using the cutting and suture technique. Complications were analyzed. RESULTS: Thirty-four (60.7%) patients reported their nasal obstruction was much improved, 17 (30.3%) reported their condition was improved, and 5 (8.9%) reported no change postoperatively. Patients reported a decrease in severity of all nasal symptoms (p < 0.05 for each). Their nasal obstruction improvement was not significantly different from that of patients managed by the cutting and suture technique. Complications after surgery included hyposmia in two cases, small septal perforation in one case, chondritis in one case, and septal abscess in one case, and all were managed successfully. No patient required revision septoplasty due to recurrence during the follow-up period. CONCLUSION: Endonasal septoplasty using caudal septal batten grafting for caudal septal deviation resulted in improvement in nasal obstruction and nasal symptoms and was associated with an acceptable complication rate.

Palatine tonsil size in obese, overweight, and normal-weight children with sleep-disordered breathing.

OBJECTIVE: To assess palatine tonsil size relative to degree of obesity in children with sleep-disordered breathing (SDB). STUDY DESIGN: Case-control study. SETTING: Tertiary care rhinology clinic. SUBJECTS AND METHODS: We compared the subjective and objective tonsil size, including tonsil height (TH), tonsil width (TW), tonsil thickness (TT), tonsil weight (TWt), and tonsil volume (TV), in 26 obese children and 26 age- and gender-matched control children with SDB, and in 29 overweight children and 29 matched controls with SDB. RESULTS: Despite similar subjective tonsil size in obese and control children, the objective tonsil size, including TH, TW, TT, and TWt, was larger in obese than in control children, and the mean TV was significantly greater in obese than in control children with SDB (8.53 +/- 3.30 mL vs 6.90 +/- 2.05 mL; 95% confidence interval [CI] of the difference 0.03-3.25; P = 0.019). In contrast, mean TV (7.38 +/- 3.43 mL vs 7.65 +/- 1.97 mL; 95% CI -1.92 to 1.37; P = 0.320) as well as the other parameters of objective palatine tonsil size, including TH, TW, TT, and TWt, did not differ significantly between overweight children and controls. CONCLUSION: Obese children with SDB had larger palatine tonsils than did normal-weight children with SDB. This finding suggests that larger palatine tonsils may have a greater effect on upper airway obstruction in obese than in normal-weight children with SDB.

Sequestering carbon dioxide into complex structures of naturally occurring gas hydrates.

Large amounts of CH4 in the form of solid hydrates are stored on continental margins and in permafrost regions. If these CH4 hydrates could be converted into CO2 hydrates, they would serve double duty as CH4 sources and CO2 storage sites. We explore here the swapping phenomenon occurring in structure I (sI) and structure II (sII) CH4 hydrate deposits through spectroscopic analyses and its potential application to CO2 sequestration at the preliminary phase. The present 85% CH4 recovery rate in sI CH4 hydrate achieved by the direct use of binary N2+CO2 guests is surprising when compared with the rate of 64% for a pure CO2 guest attained in the previous approach. The direct use of a mixture of N2+CO2 eliminates the requirement of a CO2 separation/purification process. In addition, the simultaneously occurring dual mechanism of CO2 sequestration and CH4 recovery is expected to provide the physicochemical background required for developing a promising large-scale approach with economic feasibility. In the case of sII CH4 hydrates, we observe a spontaneous structure transition of sII to sI during the replacement and a cage-specific distribution of guest molecules. A significant change of the lattice dimension caused by structure transformation induces a relative number of small cage sites to reduce, resulting in the considerable increase of CH4 recovery rate. The mutually interactive pattern of targeted guest-cage conjugates possesses important implications for the diverse hydrate-based inclusion phenomena as illustrated in the swapping process between CO2 stream and complex CH4 hydrate structure.

Two cases of post transplant lymphoproliferative disorder in lung transplant recipients.

Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after solid organ transplantation. The incidence of PTLD is greater among heart (2 approximately 13%), lung (12%) and heart/lung (5 approximately 9%) transplant recipients than among liver (2%), renal (1 approximately 3%) and bone marrow (1 approximately 2%) transplants recipients. The difference in the incidence of PTLD may be partly attributed to the higher dose of immunosuppressant therapy used for heart and lung transplantation. The Epstein-Barr virus (EBV) infection status of the donor and recipient before a transplant, and high dose of immunosuppressive drugs are considered major risk factors. Recently, 2 cases of PTLD in a single lung and a heart-lung transplantation recipient were encountered. Both patients presented with multiple pulmonary nodules in the transplanted lung, which developed 6 months and 2 years after the transplantation, respectively. Following a transthoracic lung biopsy for diagnostic confirmation, one patient underwent chemotherapy for PTLD and the other conservative care for an accompanying viral infection. Both patients showed rapid clinical deterioration, without response to treatment, and then rapidly succumbed. Herein, our experiences are reported, with a review of the literature.