Pharmacological approaches for targeting lysosomes to induce ferroptotic cell death in cancer.

Lysosomes are crucial organelles responsible for the degradation of cytosolic materials and bulky organelles, thereby facilitating nutrient recycling and cell survival. However, lysosome also acts as an executioner of cell death, including ferroptosis, a distinctive form of regulated cell death that hinges on iron-dependent phospholipid peroxidation. The initiation of ferroptosis necessitates three key components: substrates (membrane phospholipids enriched with polyunsaturated fatty acids), triggers (redox-active irons), and compromised defence mechanisms (GPX4-dependent and -independent antioxidant systems). Notably, iron assumes a pivotal role in ferroptotic cell death, particularly in the context of cancer, where iron and oncogenic signaling pathways reciprocally reinforce each other. Given the lysosomes' central role in iron metabolism, various strategies have been devised to harness lysosome-mediated iron metabolism to induce ferroptosis. These include the re-mobilization of iron from intracellular storage sites such as ferritin complex and mitochondria through ferritinophagy and mitophagy, respectively. Additionally, transcriptional regulation of lysosomal and autophagy genes by TFEB enhances lysosomal function. Moreover, the induction of lysosomal iron overload can lead to lysosomal membrane permeabilization and subsequent cell death. Extensive screening and individually studies have explored pharmacological interventions using clinically available drugs and phytochemical agents. Furthermore, a drug delivery system involving ferritin-coated nanoparticles has been specifically tailored to target cancer cells overexpressing TFRC. With the rapid advancements in understandings the mechanistic underpinnings of ferroptosis and iron metabolism, it is increasingly evident that lysosomes represent a promising target for inducing ferroptosis and combating cancer.

Andrographolide causes p53-independent HCC cell death through p62 accumulation and impaired DNA damage repair.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly lethal cancer characterized by dominant driver mutations, including p53. Consequently, there is an urgent need to search for novel therapeutic agents to treat HCC. Andrographolide (Andro), a clinically available anti-inflammatory phytochemical agent, has shown inhibitory effects against various types of cancer, including HCC. However, the underlying molecular mechanisms of its action remain poorly understood. PURPOSE: This study aims to investigate the molecular mechanisms by which p53 and p62 collectively affect Andro-induced HCC cell death, using both in vitro and in vivo models. METHODS: In vitro cellular experiments were conducted to examine the effects of Andro on cell viability and elucidate its mechanisms of action. In vivo xenograft experiments further validated the anti-cancer effects of Andro. RESULTS: Andro induced dose- and time-dependent HCC cell death while sparing normal HL-7702 hepatocytes. Furthermore, Andro caused DNA damage through the generation of reactive oxygen species (ROS), a critical event leading to cell death. Notably, HCC cells expressing p53 exhibited greater resistance to Andro-induced cell death compared to p53-deficient cells, likely due to the ability of p53 to induce G2/M cell cycle arrest. Additionally, Andro-induced p62 aggregation led to the proteasomal degradation of RAD51 and 53BP1, two key proteins involved in DNA damage repair. Consequently, silencing or knocking out p62 facilitated DNA damage repair and protected HCC cells. Importantly, disruption of either p53 or p62 did not affect the expression of the other protein. These findings were further supported by the observation that xenograft tumors formed by p62-knockout HCC cells displayed increased resistance to Andro treatment. CONCLUSION: This study elucidates the mechanistic basis of Andro-induced HCC cell death. It provides valuable insights for repurposing Andro for the treatment of HCC, regardless of the presence of functional p53.

Analysis of 7 cases of delayed diagnosis of primary upper tract urothelial carcinoma with calculi / 现代泌尿外科杂志

【Objective】 To reduce the misdiagnosis rate by analyzing the clinical data of patients with primary upper tract urothelial carcinoma (UTUC) complicated with calculi. 【Methods】 Clinical data of 7 UTUC with calculi patients treated during Sep.2018 and Apr.2022 were retrospectively analyzed, including general data, time from visit to diagnosis, imaging data, urine exudation cytological results, surgical methods, pathological stages and follow-up data. 【Results】 The ratio of male to female was 3∶4, and the mean age was 66.4 (55-72) years. The initiate imaging examination results only showed calculi, but did not indicate suspicious tumor (including 1 case with missing data). The median time from the first visit to diagnosis was 12 months (5-36 months). Of all 7 cases, 2 (2/4) were clinically diagnosed by enhanced CT, 3 (3/4) by MRI, and 2 (2/7) by positive urine exudation cytology. All patients received surgical treatment. Postoperative pathology showed 85.71% (6/7) were high-grade UTUC. Postoperative staging was T1N0M0 in 4 cases, T3N0M0 in 2 cases, and T4N2M0 in 1 case. Adjuvant chemotherapy was conducted in 2 cases. During the median follow-up of 12 months (6-41), 1 case developed multiple systemic metastases in month 9, while the other cases had no recurrence or metastasis. 【Conclusion】 For UTUC patients without obvious filling defect on imaging, especially when ipsilateral calculi were complicated, misdiagnosis should be alerted for timely treatment and better prognosis.

Comparison of complications and analysis of factors affecting renal function decline after laparoscopic radical cystectomy with different urinary diversion methods / 中华老年医学杂志

Objective:To compare the complications associated with various urinary flow diversion methods and identify the factors that contribute to the decline in renal function after radical total cystectomy for myoinfiltrating urothelial carcinoma.Methods:This study conducted a retrospective analysis on the clinical data of 46 patients with pathologically confirmed muscle-invasive bladder cancer.The patients underwent laparoscopic radical cystectomy with either ileal conduit diversion(n=21)or ureterocutaneous diversion(n=25)between January 2017 and December 2021.Perioperative data, postoperative pathology, postoperative complications, and follow-up results were compared between the two groups.Results:The study found significant differences between the two groups in terms of age[(67±6)years vs.(73±8)years, t=3.132, P=0.003], Charlson comorbidity index adjusted for age[(3.80±1.15) vs.(4.52±1.03), t=2.223, P=0.031], prognostic nutritional index[(48.81±5.74) vs.(43.64±4.74), t=3.347, P=0.002], operation time[(449±108)minutes vs.(326±130)minutes, P=0.001]], hospital stay[(20.1±11.1)days vs.(13.3±5.2)days, t=2.762, P=0.008], proportion of Clavien grade 3 or higher complications within 3 months after surgery(4/21 vs 0/25, χ2=2.105, P<0.05), and proportion of stoma-free patients(18/21 vs.5/25, χ2=6.373, P<0.01). According to Logistic multivariate analysis, perioperative blood transfusion and urinary tract infection were identified as independent risk factors for renal function decline 12 months after surgery.Escherichia coli was found to be the most common bacteria cultured from urinary tract infections in both groups after surgery. Conclusions:Laparoscopic radical cystectomy with ureterocutaneous diversion offers benefits such as shorter hospital stays and fewer perioperative complications for older and frail patients.However, a higher proportion of patients may require ureteral stenting.It is important to note that perioperative blood transfusion and urinary tract infection are major risk factors for renal function decline following radical cystectomy.

Clinical analysis of 12 cases of primary urethral carcinoma / 中华老年医学杂志

Objective:To investigate the clinical features, diagnosis, treatment and prognosis of primary urethral carcinoma.Methods:The clinical and follow-up data of 12 patients with primary urethral carcinoma admitted to Beijing Hospital from July 2016 to December 2020 were retrospectively analyzed.Results:There were four males and eight females, with an average age of 66.3(53~75)years.Nine patients underwent magnetic resonance examination before operation, and eight patients presented with abnormal urethral signals.The clinical stage of female patients was generally later than those of male patients, and all patients received surgical treatment.Four male patients did not receive post-operative adjuvant treatment, and all of them attained disease-free survival.Among the eight female patients, four patients received postoperative adjuvant radiotherapy or chemotherapy, five patients had recurrence or metastasis during follow-up, and two patients died.Conclusions:The clinical stage of female urethral cancer is later than that of male.MRI examination is beneficial to the determination of local invasion of urethral cancer.For female proximal urethral cancer and male posterior urethral cancer, radical resection has a good therapeutic effect.

Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression.

BACKGROUND: The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression. METHODS: We first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo. RESULTS: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs. CONCLUSION: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers.

Clinical efficacy of atezolizumab plus bevacizumab combined with local therapy for the treat-ment of recurrent hepatocellular carcinoma before liver transplantation / 中华消化外科杂志

Downstaging treatment by local therapy combined with systemic therapy before liver transplantation for patients with recurrent hepatocellular carcinoma (HCC) can control tumor progression and reduce tumor burden, which resulting in reducing the push-out rate of patients during the waiting period for liver transplantation, providing an oncological observation window, enabling patients of beyond Milan criteria downstaged with better survival benefit. The authors introduce the clinical experience of a case with recurrent HCC of beyond Milan criteria who under-went liver transplantation after receiving atezolizumab plus bevacizumab combined with local therapy. Results show the patient achieving pathological complete remission without postoperative rejection and obtaining a good prognosis with life status improved.

Laparoscopic Versus Open Surgery for Early-Stage Intrahepatic Cholangiocarcinoma After Mastering the Learning Curve: A Multicenter Data-Based Matched Study.

BACKGROUND: Surgical resection is the only widely accepted curative method for intrahepatic cholangiocarcinoma (ICC). However, little is known about the efficacy of laparoscopic liver resection for ICC, especially in patients with early-stage disease. The aim of this study was to compare the short-term and long-term effects of laparoscopy and open surgery for the treatment of ICC. METHODS: Data from 1,084 patients treated at three hospitals from January 2011 to December 2018 were selected and analyzed. Propensity score matching was performed to compare the long-term outcomes (overall survival and recurrence-free survival) and short-term outcomes (perioperative outcomes) of all-stage and early-stage patients. RESULTS: After matching, 244 patients (122 vs. 122) in the all-stage group and 65 patients (27 vs. 38) in the early-stage group were included. The baseline of the two groups was balanced, and no significant differences were found in sex or age. The short-term results of the laparoscopic group were better than those of the open group, including less blood loss [blood loss ≥400 ml 27 (22.1%) vs. 6 (4.92%), p<0.001 for all-stage, 12 (31.6%) vs. 2 (7.41%), p=0.042 for early stage), shorter surgery [200 (141; 249) min vs. 125 (115; 222) min, p=0.025 for early stage] and shorter hospital stay [11.0 (9.00; 16.0) days vs. 9.00 (7.00; 12.0) days, p=0.001 for all stage, 11.0 (8.50; 17.8) days vs. 9.00 (6.50; 11.0) days, p=0.011 for early stage]. Regarding long-term outcomes, no significant differences were found for all-stage patients, while there were significant differences observed for the early-stage group (p=0.013 for OS, p=0.014 for RFS). For the early-stage patients, the 1-, 3-, and 5-year OS rates of the OLR group were 84.2, 65.8, and 41.1%, respectively, and those of the LLR group were 100, 90.9, and 90.9%, respectively. The RFS rates of the OLR group were 84.2, 66.7, and 41.7%, respectively, and those of the LLR group were and 92.3, 92.3, and 92.3%, respectively. CONCLUSION: Patients treated with laparoscopy seemed to have better short-term outcomes, such as less blood loss, shorter operation duration, and shorter hospital stay, than patients undergoing open surgery. Based on the long-term results, laparoscopic treatment for early ICC may have certain advantages.

Electromagnetic field-assisted cell-laden 3D printed poloxamer-407 hydrogel for enhanced osteogenesis.

3D bioprinted hydrogel has gained enormous attention, especially in tissue engineering, owing to its attractive structure and excellent biocompatibility. In this study, we demonstrated that 3D bioprinted cell-laden 'thermoresponsive' poloxamer-407 (P407) gels have the potential to stimulate osteogenic differentiation of apical papilla stem cells (SCAPs) under the influence of low voltage-frequency (5 V-1 Hz, 0.62 mT) electromagnetic fields (EMFs). SCAPs were initially used for cell-laden 3D printing to biomimic the apical papilla of human teeth. The developed hydrogel exhibited higher mechanical strength as well as good printability, showing high-quality micro-architecture. Moreover, the as-printed hydrogels (5 mm × 5 mm) were loaded with plasminogen activator inhibitor-1 (PAI-1) for testing the combined effect of PAI-1 and EMFs on SCAP differentiation. Interestingly, the 3D hydrogels showed improved viability and differentiation of SCAPs under EMFs' influence as examined by live/dead assay and alizarin Red-S staining, respectively. Therefore, our results confirmed that P407 hydrogels are non-toxic for encapsulation of SCAPs, yielding high cell viability and accelerate the cell migration potential. The 3D hydrogels with PAI-1 exhibited high mRNA expression levels for osteogenic/odontogenic gene markers (ALP, Col-1, DSPP, and DMP-1) vis-à-vis control after 14 days of in vitro culture. Our findings suggest that 3D bioprinted P407 hydrogels are biocompatible for SCAP encapsulation, and the applied low voltage-frequency EMFs could effectively improve dental tissue regeneration, particularly for oral applications.

Evaluation of the Sensing Potential of Stem Cell-Secreted Proteins via a Microchip Device under Electromagnetic Field Stimulation.

Most bone tissue engineering models fail to demonstrate the complex cellular functions of living bone; therefore, most translational studies on bone tissue are performed in live models. To reduce the need for live models, we developed a stimulated microchip model for monitoring protein secretion during osteogenesis using human mesenchymal stem cells (hMSCs). We established a bone microchip system for monitoring the in vitro differentiation and sensing the secreted proteins of hMSCs under a sinusoidal electromagnetic field (SEMF), which ameliorates bone healing in a biomimetic natural bone matrix. A 3 V-1 Hz SEMF biophysically stimulated osteogenesis by activating ERK-1/2 and promoting phosphorylation of p38 MAPK kinases. Exposure to a 3 V-1 Hz SEMF upregulated the expression of osteogenesis-related genes and enhanced the expression of key osteoregulatory proteins. We identified 23 proteins that were differentially expressed in stimulated human bone marrow mesenchymal stem cell secretomes or were absent in the control groups. Our on-chip stimulation technology is easy to use, versatile, and nondisruptive and should have diverse applications in regenerative medicine and cell-based therapies.

Clinical efficacy and safety of docetaxel in the treatment of castration resistant prostate cancer patients over 75 years old / 中华泌尿外科杂志

Objective:To evaluate the efficacy and safety of docetaxel+ prednisone in the treatment of castrated resistant prostate cancer in patients over 75 years old.Methods:In this study, 118 metastatic castration resistant prostate cancer (mCRPC) patients over 60 years old treated in Beijing Hospital from February 2013 to December 2019 were retrospectively analyzed. The median age of the patients was 72 (65, 77)years, ECOG scores ≤2. All 118 cases had bone metastasis, 5 cases had visceral metastasis. A total of 40 patients chose docetaxel as the first-line treatment of mCRPC, and the remaining 78 patients chose docetaxel as second-line or third-line treatment. The study included 53 patients >75 years old and 65 patients aged 60-75 years. The age of patients in the two groups were 67 (63, 71) years old and 78 (76, 83) years old, the difference was statistically significant ( P<0.05). Among them, there were 24 cases with Gleason score ≤7 and 41 cases with Gleason score >7 in 60-75 years old group, and 30 cases with Gleason score ≤7 and 23 cases with Gleason score >7 in the group of >75 years old, with significant difference between the two groups ( P = 0.034). Sixty-one patients received endocrine therapy and 4 received orchiectomy in the 60-75 years old group; 43 patients received endocrine therapy and 10 received orchiectomy in the group of >75 years old, the difference was statistically significant ( P=0.035). There were 37 cases with ECOG 0 score, 25 cases with 1 scores and 3 cases with 2 scores in the group of 60-75 years old; there were 5 cases with ECOG 0 score, 38 cases with 1 score and 10 cases with 2 score in the group of >75 years old, with significant difference between the two groups ( P<0.05). There was no significant difference in PSA level[ 90 (35.5, 258) ng/ml vs. 115 (60, 296) ng/ml], G8 scale score [(14.3±2.1 vs. 13.6±1.1)], Mini-Cog score[3(2, 3) vs. 3(1, 3)], and visceral metastasis [2 cases (3.1%) vs. 3 cases (5.7%)]( P>0.05). The efficacy and safety of docetaxel in the two groups were further observed. Results:The median follow-up time was 21.5 (6, 62) months. There was no significant difference in chemotherapy cycle [(6.1±1.3) vs. (6.8±1.7)] and chemotherapy dose [(70.3±4.3) mg/m 2 vs. (66.3±5.2) mg/m 2] between the 60-75 years old group and the >75 year old group ( P> 0.05). The PSA response rate [72.3%(47/65)vs.66.0%(35/53)], pain relief rate [45.0% (9/20) vs. 54.5% (6/11)], and median progression-free survival[6.1 (1.4, 11.2) months vs. 5.9 (2.0, 12.0) months] had no statistical significance ( P>0.05). There were no deaths in the two groups during chemotherapy. The median overall survival(OS) of patients aged 60-75 years and those >75 years old who received docetaxel as first-line treatment were 26.5 (16.1, 31.3) months and 24.8 (17.5, 28.4) months, respectively ( P=0.223). The median OS of the two groups were 17.3 (13.2, 20.5) months and 15.4 (12.3, 20.0) months with docetaxel treatment as second or third line treatment ( P=0.331). There were 3 cases (4.6%) and 5 cases (9.4%) of grade 3 adverse reactions in 60-75 years group and >75 years old group, respectively. Grade 3 leukopenia occurred in 1 case time (1.5%) and 2 cases (3.8%) respectively. Grade 3 neutropenia fever occurred in 1 case time in both groups. There was no significant difference in the incidence of above complications between the two groups ( P > 0.05). Conclusions:The efficacy and safety of docetaxel + prednisone chemotherapy for mCRPC patients >75 years old were similar to those of 60-75 years old. Age should not be the absolute contraindication of docetaxel for prostate cancer chemotherapy.

The value of serum IL-23 levels in predicting the progression of metastatic prostate cancer / 中华老年医学杂志

Objective:To investigate the value of serum IL-23 in predicting the progression of prostate cancer at different stages of treatment.Methods:A total of 124 patients with metastatic prostate cancer diagnosed in Beijing Hospital from June 2018 to March 2019 were collected.Patients were TNM-staged according to the Prostate Cancer Guidelines of the European Association of Urology.Serum IL-23 levels were measured in patients with metastatic castration resistance prostate cancer(mCRPC), metastatic castration sensitive prostate cancer(mCSPC)and benign prostatic hyperplasia(BPH), respectively.Patients with mCRPC were subgrouped based on disease stability, and serum IL-23 levels were compared between the subgroups.Serum IL-23 levels in the groups were analyzed and compared with the Gleason score and the prostate-specific antigen(PSA)level.Results:The median value of serum IL-23 in the mCRPC group was 79.73(45.61, 95.63)μg/L, which was higher than that in the BPH group[30.88(15.01, 44.94)μg/L, Z=22.66, P=0.000]and the mCSPC group[46.10(35.27, 80.92)μg/L, Z=11.46, P=0.001]. Serum IL-23 levels were higher in the mCSPC group than in the BPH group( Z=7.17, P=0.007). Analysis for the subgroups showed that the median value of serum IL-23 was 110.25(88.47, 159.09)μg/L in mCRPC patients with unstable disease, which was higher than that in mCRPC patients with stable disease[46.52(44.97, 80.33)μg/L, Z=33.99, P=0.000]. There was no significant difference in serum IL-23 levels between mCRPC patients with stable disease and mCSPC patients[46.10(35.27, 80.92)μg/L]( Z=0.35, P=0.554). Conclusions:Serum IL-23 can be used as a potential biological indicator to predict the therapeutic effect of mCSPC and to predict tumor metastasis.

Comparative study of laparoscopic surgery and open surgery in the treatment of intrahepatic cholangiocarcinoma / 中华肝胆外科杂志

Objective:To compare the differences of short and long-term outcomes between laparoscopic surgery and open surgery treatment of intrahepatic cholangiocarcinoma patients.Methods:A retrospective cohort study was conducted to collect the clinical data of 118 patients with intrahepatic cholangiocarcinoma who underwent surgery in Qilu Hospital of Shandong University from January 2015 to June 2020. They were divided into laparoscopy group and open group according to the operation methods. The perioperative data, such as intraoperative surgical conditions, hospital costs, postoperative complications, postoperative blood biochemical tests, and the follow-up data of the two groups were compared.Results:In the laparoscopic group, there were 40 patients, 18 males and 22 females, aged (61.5±9.1) years. There were 78 patients in the open group, 48 males and 30 females, aged (61.2±8.3) years. The tumor size of the laparoscopic group was (4.4±1.8) cm, which was smaller than that of the open group (6.0±3.3) cm, and the differences were statistically significant ( P<0.05). In the laparoscopic group, 4 cases (10%) were converted to open surgery. The intraoperative blood loss, intraoperative blood transfusion proportion, 3 or more liver segments resection proportion and hospital costs of laparoscopic group were lower than those of open group [200.0(100.0, 261.8) ml vs. 300.0(100.0, 400.0) ml, 5.0%(2/40) vs. 26.9%(21/78), 37.5%(15/40) vs. 66.7%(52/78), (6.2±2.0) wan yuan vs. (7.2±2.3) wan yuan], the differences were statistically significant (all P<0.05). There were no significant differences in the incidence of postoperative complications between the two groups ( P>0.05). On the first post-operative day, ALT serum level and the third post-operative day TBil serum level in the laparoscopic group were lower than those in the open group [188.5(130.5, 274.0) U/L vs. 320.0(144.0, 427.0) U/L, 26.4(18.3, 26.4) μmol/L vs. 31.6(18.8, 37.5) μmol/l], the differences were statistically significant ( P<0.05). There were no significant differences in 1-year and 2-year overall survival rate and disease-free survival rate between the two groups ( P>0.05). Conclusion:Compared with open surgery, laparoscopic surgery in the treatment of intrahepatic cholangiocarcinoma has better short-term outcomes, and can achieve similar results in medium- or long-term outcomes.

Non-Cell-Autonomous Activity of the Hemidesmosomal Protein BP180/Collagen XVII in Granulopoiesis in Humanized NC16A Mice.

BP180 (also termed type XVII collagen) is a hemidesmosomal protein and plays a critical role in cell-cell matrix adhesion in the skin; however, its other biological functions are largely unclear. In this study, we generated a BP180 functional-deficient mouse strain by deleting its extracellular domain of humanized NC16A (termed ΔNC16A mice). We found that BP180 is expressed by bone marrow mesenchymal stem cells (BM-MSC), and its functional deficiency leads to myeloid hyperplasia. Altered granulopoiesis in ΔNC16A mice is through bone marrow stromal cells evidenced by bone marrow transplantation. Furthermore, the level of G-CSF in bone marrow and circulation were significantly increased in ΔNC16A mice as compared with wild-type mice. The increased G-CSF was accompanied by an increased activation of the NF-κB signaling pathway in bone marrow and BM-MSC of ΔNC16A mice. Blockade of G-CSF restored normal granulopoiesis in ΔNC16A mice. Inhibition of NF-κB signaling pathway significantly reduces the release of G-CSF from ΔNC16A BM-MSC in vitro and the level of serum G-CSF in ΔNC16A mice. To our knowledge, these findings provide the first direct evidence that BP180 plays an important role in granulopoiesis through regulating NF-κB signaling pathway in BM-MSC.

Is laparoscopic hepatectomy suitable for giant hepatic hemangioma larger than 10 cm in diameter?

BACKGROUND: Surgical treatment of giant hepatic hemangioma larger than 10 cm in diameter often requires major laparoscopic liver resection (LLR), which is very difficult and has a high risk of bleeding. There is no consensus as to whether giant hepatic hemangioma is an indication or a contraindication for laparoscopic surgery. METHODS: From 2011/09 to 2018/05, 58 patients with giant hepatic hemangioma larger than 10 cm underwent laparoscopic surgery. They were divided into high-difficulty (HD) group and low-difficulty (LD) group according to the operation difficulty score. The perioperative data of the two groups were analyzed and compared. RESULTS: There were 30 patients in the LD group and 28 in the HD group. No differences were showed in sex, age, ASA grade, tumor size, operation time, conversion rate, intraoperative and post-operative blood transfusion rate, and post-operative complications between the two groups. The amount of bleeding in the HD group was significantly higher than that in the LD group (285.7 ± 224.0 vs 189.6 ± 157.6 ml, p = 0.007). The time of hepatic hilar occlusion in the HD group was longer than that in the LD group (25.4 ± 8.8 vs 20.6 ± 7.3 min, p = 0.001), and the rate of hepatic hilar occlusion in the HD group was also higher than that in the LD group (71.4% vs 33.3%, p = 0.004). The incidence of hospitalization days and discharge time in the LD group were shorter than those in the HD group (6.3 ± 1.6 vs 8.2 ± 1.4 days, p = 0.000; 16.4 ± 5.5 vs 21.9 ± 4.6 h, p = 0.019). There was no significant difference in enzymatic parameters between the two groups after operation. CONCLUSIONS: Although there are great difficulties and risks objectively, laparoscopic treatment of giant hepatic hemangioma is safe and feasible.

Spine Computed Tomography to Magnetic Resonance Image Synthesis Using Generative Adversarial Networks : A Preliminary Study

Objective@#: To generate synthetic spine magnetic resonance (MR) images from spine computed tomography (CT) using generative adversarial networks (GANs), as well as to determine the similarities between synthesized and real MR images. @*Methods@#: GANs were trained to transform spine CT image slices into spine magnetic resonance T2 weighted (MRT2) axial image slices by combining adversarial loss and voxel-wise loss. Experiments were performed using 280 pairs of lumbar spine CT scans and MRT2 images. The MRT2 images were then synthesized from 15 other spine CT scans. To evaluate whether the synthetic MR images were realistic, two radiologists, two spine surgeons, and two residents blindly classified the real and synthetic MRT2 images. Two experienced radiologists then evaluated the similarities between subdivisions of the real and synthetic MRT2 images. Quantitative analysis of the synthetic MRT2 images was performed using the mean absolute error (MAE) and peak signal-to-noise ratio (PSNR). @*Results@#: The mean overall similarity of the synthetic MRT2 images evaluated by radiologists was 80.2%. In the blind classification of the real MRT2 images, the failure rate ranged from 0% to 40%. The MAE value of each image ranged from 13.75 to 34.24 pixels (mean, 21.19 pixels), and the PSNR of each image ranged from 61.96 to 68.16 dB (mean, 64.92 dB). @*Conclusion@#: This was the first study to apply GANs to synthesize spine MR images from CT images. Despite the small dataset of 280 pairs, the synthetic MR images were relatively well implemented. Synthesis of medical images using GANs is a new paradigm of artificial intelligence application in medical imaging. We expect that synthesis of MR images from spine CT images using GANs will improve the diagnostic usefulness of CT. To better inform the clinical applications of this technique, further studies are needed involving a large dataset, a variety of pathologies, and other MR sequence of the lumbar spine.

Comparison of clinical efficacy of femoral calcar prosthesis replacement and intramedullary nail in the treatment of elderly patients with intertrochanteric fracture / 中国骨伤

OBJECTIVE@#To analyze the clinical efficacy of hip arthroplasty with femoral calcar prosthesis and proximal femoral nail fixation(PFNA) in the treatment of elderly patients(≥80 years old) with unstable intertrochanteric fractures(Evans Ⅲ, Ⅳ).@*METHODS@#From June 2016 to March 2018, 60 elderly patients with unstable intertrochanteric fractures treated with prosthetic replacement and PFNA were retrospectively analyzed. According to the surgical methods, they were divided into PFNA group and prosthesis group. In PFNA group there were including 21 males and 15 females, with an average age of(84.3± 2.9) years old;in the prosthetic group, there were 10 males and 14 females with an average age of (82.9±2.4) years old. The operation time, hemoglobin difference between preoperative and postoperative 1 day, postoperative ambulation time, hospitalization time and complications were observed and compared between the two groups. Harris hip score was performed 3 and 12 months after operation.@*RESULTS@#All patients were followed up for 12 to 24 months (19.3±4.8) months. One patient in the prosthesis group died of lung cancer one year later and the follow-up was terminated. The operation time of prosthetic group was longer than that of PFNA group(@*CONCLUSION@#The elderly patients with intertrochanteric arthroplasty can reduce the burden of intertrochanteric arthroplasty and improve the quality of life.

CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis.

The HER2-specific monoclonal antibody (mAb), trastuzumab, has been the mainstay of therapy for HER2+ breast cancer (BC) for approximately 20 years. However, its therapeutic mechanism of action (MOA) remains unclear, with antitumor responses to trastuzumab remaining heterogeneous and metastatic HER2+ BC remaining incurable. Consequently, understanding its MOA could enable rational strategies to enhance its efficacy. Using both murine and human versions of trastuzumab, we found its antitumor activity dependent on Fcγ receptor stimulation of tumor-associated macrophages (TAMs) and antibody-dependent cellular phagocytosis (ADCP), but not cellular cytotoxicity (ADCC). Trastuzumab also stimulated TAM activation and expansion, but did not require adaptive immunity, natural killer cells, and/or neutrophils. Moreover, inhibition of the innate immune ADCP checkpoint, CD47, significantly enhanced trastuzumab-mediated ADCP and TAM expansion and activation, resulting in the emergence of a unique hyperphagocytic macrophage population, improved antitumor responses, and prolonged survival. In addition, we found that tumor-associated CD47 expression was inversely associated with survival in HER2+ BC patients and that human HER2+ BC xenografts treated with trastuzumab plus CD47 inhibition underwent complete tumor regression. Collectively, our study identifies trastuzumab-mediated ADCP as an important antitumor MOA that may be clinically enabled by CD47 blockade to augment therapeutic efficacy.

The dysfunction of BP180/collagen XVII in keratinocytes promotes melanoma progression.

BP180, also termed collagen XVII, is a hemidesmosomal transmembrane glycoprotein expressed in basal keratinocytes, and functions as a cell-matrix adhesion molecule in the dermal-epidermal junction of the skin. Its function, other than cell-matrix adhesion, remains unclear. We generated a mouse strain with BP180 dysfunction (termed ∆NC16A), which develops spontaneous skin inflammation accompanied by an influx of myeloid derived suppressor cells (MDSCs). We used the B16 mouse melanoma model to demonstrate that BP180 dysfunction in either skin or basal keratinocytes promotes MDSC influx into skin and tumor progression. MDSC depletion reduced tumor progression in ∆NC16A mice, demonstrating a critical role for BP180 dysfunction-driven MDSCs in melanoma progression. This study provides the first direct evidence that BP180, a cell-cell matrix adhesion molecule, possesses antitumor function through modulating infiltration of MDSCs. Basal keratinocytes actively participate in skin microenvironment changes caused by BP180 dysfunction. ∆NC16A mice could be a new animal model to study the melanoma microenvironment.

BP180 dysfunction triggers spontaneous skin inflammation in mice.

BP180, also known as collagen XVII, is a hemidesmosomal component and plays a key role in maintaining skin dermal/epidermal adhesion. Dysfunction of BP180, either through genetic mutations in junctional epidermolysis bullosa (JEB) or autoantibody insult in bullous pemphigoid (BP), leads to subepidermal blistering accompanied by skin inflammation. However, whether BP180 is involved in skin inflammation remains unknown. To address this question, we generated a BP180-dysfunctional mouse strain and found that mice lacking functional BP180 (termed ΔNC16A) developed spontaneous skin inflammatory disease, characterized by severe itch, defective skin barrier, infiltrating immune cells, elevated serum IgE levels, and increased expression of thymic stromal lymphopoietin (TSLP). Severe itch is independent of adaptive immunity and histamine, but dependent on increased expression of TSLP by keratinocytes. In addition, a high TSLP expression is detected in BP patients. Our data provide direct evidence showing that BP180 regulates skin inflammation independently of adaptive immunity, and BP180 dysfunction leads to a TSLP-mediated itch. The newly developed mouse strain could be a model for elucidation of disease mechanisms and development of novel therapeutic strategies for skin inflammation and BP180-related skin conditions.