Intravenous calcitriol administration improves the liver redox status and attenuates ferroptosis in mice with high-fat diet-induced obesity complicated with sepsis.

Obesity aggravates ferroptosis, and vitamin D (VD) may inhibit ferroptosis. We hypothesized that weight reduction and/or calcitriol administration have benefits against the sepsis-induced liver redox imbalance and ferroptosis in obese mice. Mice were fed a high-fat diet for 11 weeks, then half of the mice continued to consume the diet, while the other half were transferred to a low-energy diet for 5 weeks. After feeding the respective diets for 16 weeks, sepsis was induced by cecal ligation and puncture (CLP). Septic mice were divided into four experimental groups: OS group, obese mice injected with saline; OD group, obese mice with calcitriol; WS group, weight-reduction mice with saline; and WD group, weight-reduction mice with calcitriol. Mice in the respective groups were euthanized at 12 or 24 h after CLP. Results showed that the OS group had the highest inflammatory mediators and lipid peroxide levels in the liver. Calcitriol treatment reduced iron content, enhanced the reduced glutathione/oxidized glutathione ratio, upregulated nuclear factor erythroid 2-related factor 2, ferroptosis-suppressing protein 1, and solute carrier family 7 member 11 expression levels. Also, mitochondrion-associated nicotinamide adenine dinucleotide phosphate oxidase 1, peroxisome proliferator-activated receptor-γ coactivator 1, hypoxia-inducible factor-1α, and heme oxidase-1 expression levels increased in the late phase of sepsis. These results were not noted in the WS group. These findings suggest that calcitriol treatment elicits a more-balanced glutathione redox status, alleviates liver ferroptosis, and enhances mitochondrial biogenesis-associated gene expressions. Weight reduction alone had minimal influences on liver ferroptosis and mitochondrial biogenesis in obese mice with sepsis.

Imaging Characteristics and Interpretation Strategy for Renal Hyperparathyroidism: A Retrospective 4-Dimensional Computed Tomography Study.

OBJECTIVE: Parathyroidectomy treats uncontrolled renal hyperparathyroidism (RHPT), requiring identification of all glands. Three types of enhancement are proposed. Type A lesions have higher arterial phase attenuation than the thyroid, type B lesions lack higher arterial phase attenuation but have lower venous phase attenuation, and type C lesions have neither higher arterial phase attenuation nor lower venous phase attenuation than the thyroid. We aimed to outline the image features of problematic parathyroid glands in RHPT and propose a 4-dimensional computed tomography (4DCT) interpretation algorithm. METHODS: This retrospective study involved data collection from patients with RHPT who underwent preoperative 4DCT for parathyroidectomy between January and November 2022. Pathologically confirmed parathyroid lesions were retrospectively identified on 4DCT according to the location and size described in the surgical notes. The attenuation of parathyroid lesions and the thyroid glands was assessed in 3 phases, and demographic data of the patients were collected. RESULTS: Ninety-seven pathology-proven parathyroid glands from 27 patients were obtained, with 86 retrospectively detected on 4DCT. In the arterial phase, the attenuation of parathyroid lesions in RHPT did not exceed that of the thyroid gland (P < .001). In the venous phase, parathyroid lesions demonstrated lower attenuation than the thyroid gland (P < .001). A total of 81 parathyroid lesions (94.2%) exhibited type B patterns. CONCLUSION: Unlike primary hyperparathyroidism, lesions in RHPT exhibited more type B enhancement, making them less readily identifiable in the arterial phase. Therefore, we propose a distinct imaging interpretation strategy to locate these problematic glands more efficiently.

Immunocyte profiling changes in patients received epidural versus intravenous analgesia after pancreatectomy: A randomized controlled trial.

BACKGROUND: Perioperative immunosuppressants, such as surgical stress and opioid use may downregulate anti-cancer immunocytes for patients undergoing pancreatectomy. Thoracic epidural analgesia (TEA) may attenuate these negative effects and provide better anti-cancer immunocyte profile change than intravenous analgesia using opioid. METHODS: We randomly assigned 108 adult patients undergoing pancreatectomy to receive one of two 72-h postoperative analgesia protocols: one was TEA, and the other was intravenous patient-controlled analgesia (IV-PCA). The perioperative proportional changes of immunocytes relevant to anticancer immunity-namely natural killer (NK) cells, cytotoxic T cells, helper T cells, mature dendritic cells, and regulatory T (Treg) cells were determined at 1 day before surgery, at the end of surgery and on postoperative day 1,4 and 7 using flow cytometry. In addition, the progression-free survival and overall survival between the two groups were compared. RESULTS: After surgery, the proportions of NK cells and cytotoxic T cells were significantly decreased; the proportion of B cells and mature dendritic cells and Treg cells were significantly increased. However, the proportions of helper T cells exhibited no significant change. These results were comparable between the two groups. Furthermore, there were no significant differences in progression-free survival (52.75 [39.96] and 57.48 [43.66] months for patients in the TEA and IV-PCA groups, respectively; p = 0.5600) and overall survival (62.71 [35.48] and 75.11 [33.10] months for patients in the TEA and IV-PCA groups, respectively; p = 0.0644). CONCLUSIONS: TEA was neither associated with favorable anticancer immunity nor favorable oncological outcomes for patients undergoing pancreatectomy.

Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes. METHODS: We examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)-positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)-AGR2 axis in mediating communication between CAFs and PNET cells was investigated. RESULTS: αSMA-positive and platelet-derived growth factor-α-positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis. CONCLUSION: CAFs drive the growth and metastasis of aggressive PNETs. The CXCR4-SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment.

Comparison of safety, efficacy, and patient satisfaction with thermal ablation versus endoscopic thyroidectomy for benign thyroid nodules in a propensity-matched cohort.

BACKGROUND: Thyroid nodules (TNs) often require intervention due to symptomatic or cosmetic concerns. Radiofrequency ablation (RFA) has shown promise as a treatment option, offering potential advantages without neck scars. Recently, the scarless treatment alternative of transoral endoscopic thyroidectomy vestibular approach (TOETVA) has emerged. When surgery can be performed in a scarless manner, it remains unclear whether ablation is still the preferred treatment choice. This study aims to compare the safety, efficacy, and patient satisfaction of RFA and TOETVA. STUDY DESIGN: A retrospective data analysis was conducted on patients treated with RFA or TOETVA for unilateral benign TNs between December 2016 and September 2021. Propensity score matching was employed to create comparable groups. Various clinicopathologic parameters, treatment outcomes, and costs were assessed. RESULTS: Of the 2814 nonfunctional thyroid nodules treated during this period, 642 were benign and unilateral. A total of 121 and 100 patients underwent thermal ablation and transoral endoscopic thyroidectomy, respectively. After matching, 84 patients were selected for each group. Both RFA and TOETVA demonstrated low complication rates, with unique complications associated with each procedure. Treatment time (30.8±13.6 vs. 120.7±36.5 min, P <0.0001) was shorter in the RFA group. Patient satisfaction (significant improvement: 89.3% vs. 61.9%, P <0.0001) and cosmetic results (cosmetic score 1-2: 100.0% vs. 54.76%, P <0.0001) favored TOETVA. RFA was found to be less costly for a single treatment, but the cost of retreatment should be considered. The histological diagnoses post-TOETVA revealed malignancies in 9 out of 84 cases, underscoring the significance of follow-up assessments. CONCLUSION: Scarless procedures, RFA and TOETVA, are effective for treating unilateral benign TNs, each with unique advantages and drawbacks. While RFA is cheaper for a single treatment, TOETVA offers superior cosmetic results and patient satisfaction. Further research is needed to evaluate long-term safety and cost-effectiveness. It is crucial to remain vigilant about the possibility of malignancy despite benign cytology pre-treatment.

Placement of Nasogastric Tubes in Pancreaticoduodenectomy Patients: Switching from Immediate Intraoperative Removal to Avoiding Unnecessary Perioperative Use.

BACKGROUND: The placement of nasogastric tubes (NGTs) in abdominal surgery has been adopted for decades to attenuate ileus and prevent aspiration pneumonia. In the recent era, the guidelines recommend not using NGT routinely, and even in pancreaticoduodenectomy (PD), immediate removal of NGT in operating rooms (ORs) was suggested. However, the clinical outcome and safety of abandoning NGT during the pre-PD and intra-PD periods remain unknown. METHODS: We conducted a single-center retrospective review on adult PD patients aged between 20 and 75 years from 2013 to 2022. The study population was grouped into the NGT group (NGT was placed before PD and immediately removed in the ORs) and the non-NGT group (NGT was not placed preoperatively). Safety was evaluated by the number of adverse events. The primary aim of this study is to evaluate the need of NGT insertion in ORs among PD patients. RESULTS: The case numbers in the NGT and non-NGT groups were 391 and 578, respectively. No case in the non-NGT group needed the intraoperative insertion of NGT. The rate of pulmonary complications was 2.3% in the NGT group compared to 1.6% in the non-NGT group (P = 0.400). Furthermore, there were no significant differences in terms of rates of major complications (12.8% vs. 9.3%, P = 0.089) or mortality (1.0% vs. 1.0%, P =0.980) between the two groups. The rates of the postoperative insertion of NGT in the NGT and non-NGT groups were 2.6% and 2.8% (P = 0.840), respectively. CONCLUSION: For selected PD patients, the placement of NGT during pre-PD and intra-PD periods may be safely omitted. This primary study is considered the first foundation stone in the extension of the element of no NGT in PD.

Calcitriol attenuates poly(I:C)-induced lung injury in obese mice via modulating toll-like receptor 3- and renin-angiotensin system-associated signal pathways.

This study investigated the effects of calcitriol on polyinosinic-polycytidylic acid (poly(I:C))-induced acute lung injury (ALI) and its association with Toll-like receptor 3 (TLR3) and renin-angiotensin system (RAS) signal pathways in obese mice. Normal mice were fed a high-fat diet to induce obesity. Obese mice were divided into four groups: SS group, intratracheally instilled with saline and intravenous (IV) saline injection via tail vein; SD group, instilled with saline and IV calcitriol injection; PS group, instilled with poly(I:C) and IV saline injection; and PD group, instilled with poly(I:C) and IV calcitriol injection. All mice were sacrificed 12 or 24 h after poly(I:C) stimulation. The results showed that poly(I:C) instillation led to increased production of systemic inflammatory cytokines. In the lungs, the population of macrophages decreased, while more neutrophils were recruited. TLR3-associated genes including IRF3, nuclear factor-κB, interferon-ß and phosphorylated IRF3 expression levels, were upregulated. The RAS-associated AT1R and ACE2 protein levels increased, whereas AT2R, Ang(1-7), and MasR levels decreased. Also, reduced tight junction (TJ) proteins and elevated lipid peroxide levels were observed 24 h after poly(I:C) stimulation. Compared to the PS group, the PD group exhibited reduced systemic and lung inflammatory cytokine levels, increased macrophage while decreased neutrophil percentages, downregulated TLR3-associated genes and phosphorylated IRF3, and polarized toward the RAS-AT2R/Ang(1-7)/MasR pathway in the lungs. Higher lung TJ levels and lower injury scores were also noted. These findings suggest that calcitriol treatment after poly(I:C) instillation alleviated ALI in obese mice possibly by downregulating TLR3 expression and tending toward the RAS-associated anti-inflammatory pathway.

Potential therapeutic implications of calcitriol administration and weight reduction on CD4 T cell dysregulation and renin angiotensin system-associated acute lung injury in septic obese mice.

This study investigated the effects of weight reduction and/or calcitriol administration on regulating CD4 T cell subsets and renin-angiotensin system (RAS)-associated acute lung injury (ALI) in obese mice with sepsis. Half of the mice were fed a high-fat diet for 16 weeks, half of them had high-fat diet for 12 weeks then were transferred to a low-energy diet for 4 weeks. After feeding the respective diets, cecal ligation and puncture (CLP) were performed to induce sepsis. There were four sepsis groups: OSS group, obese mice injected with saline; OSD group, obese mice given calcitriol; WSS group, mice with weight reduction and saline; WSD group, mice with weight reduction and calcitriol. Mice were sacrificed after CLP. The findings showed that CD4 T subsets distribution did not differ among the experimental groups. Calcitriol-treated groups had higher RAS-associated AT2R, MasR, ACE2, and angiopoietin 1-7 (Ang(1-7)) levels in the lungs. Also, higher tight junction proteins were noted 12 h after CLP. At 24 h post-CLP, weight reduction and/or calcitriol treatment reduced plasma inflammatory mediator production. Calcitriol-treated groups had higher CD4/CD8, T helper (Th)1/Th2 and lower Th17/regulatory T (Treg) ratios than the groups without calcitriol. In the lungs, calcitriol-treated groups had lower AT1R levels, whereas the RAS anti-inflammatory protein levels were higher than those groups without calcitriol. Lower injury scores were also noted at this time point. These findings suggested weight reduction decreased systemic inflammation. However, calcitriol administration produced a more-balanced Th/Treg distribution, upregulated the RAS anti-inflammatory pathway, and attenuated ALI in septic obese mice.

Synergic evacuation device helps smoke control during endoscopic thyroid surgery.

BACKGROUND: Surgical plumes in small cavities, such as transoral endoscopic thyroid surgery, have never been satisfactorily resolved. We aimed to study the use of a smoke evacuation system and evaluate its efficacy, including the field of view and operating time. STUDY DESIGN: We retrospectively reviewed 327 consecutive patients who underwent endoscopic thyroidectomy. They were separated into 2 groups based on whether the smoke evacuation system was used. To reduce the possible experience bias, only patients 4 months before and after implementing the evacuation system were included. Recorded endoscopic videos were evaluated, including the field of view, the incidence of scope clearance, and time spent during air-pocket creation. RESULTS: Overall, there were 64 patients with a median age of 43.59 years and a median body mass index of 22.87 kg/m2, including 54 women, 21 thyroid cancers, and 61 hemithyroidectomies. The operative duration was comparable between the groups. The group where the evacuation system was used scored more as good in terms of endoscopic views (8/32, 25% vs 1/32, 3.13%, P = .01), fewer incidences of endoscope lens pull out for clearance (3.5 vs 6.0 times, P < .01), less time for clear view after energy device activation (2.67 vs 5.00 seconds, P < .01), and less time spent (8.67 vs 12.38 minutes, P < .01) during air-pocket creation. CONCLUSION: In conjunction with the synergy function of energy devices, evacuators enhance the field of view and optimize the time spent in the real clinical setting of low-pressure and small-space endoscopic thyroid procedures, in addition to the benefit of reducing smoke harm.

Novel Non-duct-to-Mucosa Pancreaticojejunostomy Reconstruction After Pancreaticoduodenectomy: Focus on the Occurrence of Post-pancreatectomy Hemorrhage and Intra-abdominal Abscess.

BACKGROUND: Postoperative pancreatic fistulas (POPFs) are considered inevitable in some patients after pancreaticoduodenectomy (PD), and measures to minimize their clinical impact are needed. Postpancreatectomy hemorrhage (PPH) and intra-abdominal abscess (IAA) are the most severe POPF-related complications, and concomitant leakage of contaminated intestinal content is considered the main cause. An innovative method, modified non-duct-to-mucosa pancreaticojejunostomy (TPJ), was created to prevent concomitant leakage of intestinal content, and its effectiveness was compared between two periods. METHODS: All PD patients undergoing pancreaticojejunostomy from 2012 to 2021 were included. The TPJ group consisted of 529 patients recruited from January 2018 to December 2021. A total of 535 patients receiving the conventional method (CPJ) from January 2012 to June 2017 were used as a control group. PPH and POPF were defined according to the International Study Group of Pancreatic Surgery definition, but only PPH grade C was included for analysis. An IAA was defined as a collection of postoperative fluid managed by CT-guided drainage with documental culture. RESULTS: There were no significant differences in the rate of POPF between the two groups (46.0% vs. 44.8%; p = 0.700). Furthermore, the percentages of bile in the drainage fluid in the TPJ and CPJ groups were 2.3% and 9.2%, respectively (p < 0.001). Lower proportions of PPH (0.9% vs. 6.5%; p < 0.001) and IAA (5.7% vs. 10.8%; p < 0.001) were observed for TPJ than for CPJ. On adjusted models, TPJ was significantly associated with a lower rate of PPH (odds ratio [OR] 0.132, 95% confidence interval [CI] 0.051-0.343; p < 0.001) and IAA (OR 0.514, 95% CI 0.349-0.758; p = 0.001) than CPJ. CONCLUSIONS: TPJ is feasible to be performed and is associated with a similar rate of POPF but a lower percentage of concomitant bile in the drainage fluid and subsequent rates of PPH and IAA than CPJ.

Can Kidney Organoid Xenografts Accelerate Therapeutic Development for Genetic Kidney Disorders?

A number of genetic kidney diseases can now be replicated experimentally, using kidney organoids generated from human pluripotent stem cells. This methodology holds great potential for drug discovery. Under in vitro conditions, however, kidney organoids remain developmentally immature, develop scarce vasculature, and may contain undesired off-target cell types. Those critical deficiencies limit their potential as disease-modeling tools. Orthotopic transplantation under the kidney capsule improves the anatomic maturity and vascularization of kidney organoids, while reducing off-target cell content. The improvements can translate into more accurate representations of disease phenotypes and mechanisms in vivo . Recent studies using kidney organoid xenografts highlighted the unique potential of this novel methodology for elucidating molecular mechanisms driving monogenic kidney disorders and for the development ofnovel pharmacotherapies.

Maintenance therapy of low-dose nivolumab, S-1, and leucovorin in metastatic pancreatic adenocarcinoma with a germline mutation of MSH6: A case report.

Immune checkpoint inhibitors (ICIs) provide substantial benefits to a small subset of patients with advanced cancer with mismatch repair deficiency (MMRD) or microsatellite instability (MSI), including patients with pancreatic ductal adenocarcinoma (PDAC). However, the long duration of ICI treatment presents a considerable financial burden. We present the case of a 63-year-old woman with metastatic PDAC refractory to conventional chemotherapy. Genetic analyses identified an MSH6 germline mutation and a high tumor mutation burden (TMB). Complete response (CR) was achieved after a short course of low-dose nivolumab (20 mg once every 2 weeks) with chemotherapy. CR was maintained for over 1 year with low-dose nivolumab and de-escalated chemotherapy without any immune-related adverse events. This case supports the further exploration of low-dose, affordable ICI-containing regimens in patients with advanced MSI-high/TMB-high cancer.

Transcutaneous Laryngeal Ultrasonography for Assessing Vocal Cord Twitch Response in Thyroid Operation during Predissection Vagus Nerve Stimulation.

BACKGROUND: In this study, we aimed to report our experience with the use of intraoperative transcutaneous laryngeal ultrasonography (TLUSG) to evaluate the vocal cord twitch response during predissection vagus nerve stimulation in thyroid surgeries and examine the reliability of this technique when compared with that of laryngeal twitch palpation (LTP). STUDY DESIGN: The prospective data collection of consecutive patients who underwent open thyroidectomy with intraoperative neuromonitoring (IONM) was reviewed retrospectively. We recorded the electromyographic activity and assessed the vocal cord twitch response on LTP, TLUSG. We compared the accessibility, sensitivity, and specificity of the techniques. RESULTS: A total of 110 patients (38 men and 72 women) with 134 nerves at risk were enrolled. The vocal cord was assessable by TLUSG in 103 (93.6%) patients and by LTP in 64 (59.1%) patients. Two patients showed negative predissection IONM signal but positive on TLUSG and the presence of laryngeal twitch response confirmed by laryngoscopy. Fourteen patients showed positive IONM signals and presence of the vocal cord twitch response on TLUSG but not on LTP. The sensitivity and specificity were 70.21% and 100%, respectively, for LTP, and those both were 100% for TLUSG. For patients who could be assessed using both techniques, TLUSG had better accuracy than LTP (100% vs 80.33%, p = 0.0005). CONCLUSIONS: The innovative intraoperative application of TLUSG is better for evaluating the laryngeal twitch response than LTP. This technique provides practical troubleshooting guidance for patients with no IONM signals during predissection vagus nerve stimulation.

Practice Patterns and Learning Curve in Transoral Endoscopic Thyroidectomy Vestibular Approach With Neuromonitoring.

Objectives: Intraoperative neuromonitoring has not been routinely applied in early experience with the transoral endoscopic thyroidectomy vestibular approach (TOETVA). Because the preparation and surgical interventions are much different from conventional thyroidectomies, most endocrine surgeons willing to adapt to TOETVA lack access to information regarding the practice pattern and proficiency in the learning curve. We aimed to investigate the outcomes and to define the learning curve for TOETVA in this study. Methods: A retrospective analysis was used on patients who underwent TOETVA at our hospital between December 2016 and July 2019. The cumulative sum graphic model was used to implement the learning curve as a surrogate for procedural proficiency. Results: The 119 patients had a mean age of 44.65 years and a mean body mass index of 22.49 k/m2, including 107 women, 20 thyroiditis, and 106 hemithyroidectomy. The learning curve revealed two phases, an initial (35 cases) and a mature (84 cases) phase, for surgeons based on operation time (144.2 vs. 114.2 min, p = 0.0001). There were more bilateral thyroidectomies (15.5% vs. 0, p = 0.0100), larger indicated nodules (6.06 cm3vs. 3.32 cm3, p = 0.0468), or larger thyroids to resect (16.38 cm3vs. 8.75 cm3, p = 0.0001) in the mature phase. Procedure-related complications decreased significantly in the mature phase in comparison to the initial phase (3.57% vs. 31.43%, p = 0.0001). Conclusions: The learning curve of TOETVA with neuromonitoring is 35 cases. With the accumulation of proficiency, the indications will expand. Step-by-step improvements from the experience of each case can reduce procedure-related complications.

Negative prognostic implications of splenomegaly in nivolumab-treated advanced or recurrent pancreatic adenocarcinoma.

Immune checkpoint inhibitors have limited efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). We investigated prognostic markers for nivolumab-based therapy in advanced or recurrent PDAC. Consecutive patients receiving nivolumab-based therapy at our institution between 2015 and 2020 were evaluated. Overall survival (OS) was analyzed through univariate and multivariate analyses. Spleen volume was estimated from the width, thickness, and length of the spleen. A total of 45 patients were identified. Biweekly nivolumab was administered as monotherapy (n = 5) or in combination with chemotherapy or targeted therapy (n = 40). Among 31 evaluable patients, the response and disease control rates were 7% and 36%, respectively. The baseline median spleen volume was 267 (110-674) mL. Patients with spleens ≥267 mL had significantly shorter median OS (1.9 months, 95% confidence interval [CI], 1.0-2.7) than did those with smaller spleens (8.2 months, 95% CI, 5.6-10.8; P = .003). In the multivariate analysis, spleen volume of <267 mL, ≤2 lines of prior chemotherapy, ECOG performance status of 0-2, add-on nivolumab with stable disease after prior therapy, concomitant or sequential cell therapy, high lymphocyte count, and total bilirubin <1 mg/dL were independent favorable prognostic factors for OS. In the control groups of patients receiving gemcitabine-based chemotherapy (n = 142) or FOLFIRINOX regimen (n = 24), spleen volume exhibited no prognostic significance. In heavily pretreated PDAC, a large spleen may predict poor OS following nivolumab-based immunotherapy. Studies with larger cohorts should confirm the prognostic value of spleen volume.

C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin αv.

Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related death. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Here we showed that C1GALT1 was overexpressed in 85% (107/126) of PDAC tumors compared with adjacent non-tumor tissues. High expression of C1GALT1 was associated with poor disease-free and overall survival (n = 99). C1GALT1 knockdown using siRNA suppressed cell viability, migration, and invasion as well as increased gemcitabine sensitivity in PDAC cells. In contrast, C1GALT1 overexpression enhanced cell migration and invasion. In subcutaneous and pancreatic orthotopic injection models, C1GALT1 knockdown decreased tumor growth and metastasis of PDAC cells in NOD/SCID mice. Mechanistically, C1GALT1 knockdown dramatically suppressed cell-extracellular matrix (ECM) adhesion, which was associated with decreased phosphorylation of FAK at Y397/Y925 and changes in O-glycans on integrins including the ß1, αv, and α5 subunits. Using functional blocking antibodies, we identified integrin αv as a critical factor in C1GALT1-mediated invasiveness of PDAC cells. In conclusion, this study not only reveals that C1GALT1 could be a potential therapeutic target for PDAC but also provides novel insights into the role of O-glycosylation in the α subunits of integrins.

Humanized COVID-19 decoy antibody effectively blocks viral entry and prevents SARS-CoV-2 infection.

To circumvent the devastating pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a humanized decoy antibody (ACE2-Fc fusion protein) was designed to target the interaction between viral spike protein and its cellular receptor, angiotensin-converting enzyme 2 (ACE2). First, we demonstrated that ACE2-Fc could specifically abrogate virus replication by blocking the entry of SARS-CoV-2 spike-expressing pseudotyped virus into both ACE2-expressing lung cells and lung organoids. The impairment of viral entry was not affected by virus variants, since efficient inhibition was also observed in six SARS-CoV-2 clinical strains, including the D614G variants which have been shown to exhibit increased infectivity. The preservation of peptidase activity also enables ACE2-Fc to reduce the angiotensin II-mediated cytokine cascade. Furthermore, this Fc domain of ACE2-Fc was shown to activate NK cell degranulation after co-incubation with Spike-expressing H1975 cells. These promising characteristics potentiate the therapeutic prospects of ACE2-Fc as an effective treatment for COVID-19.

Pancreatic neck transection using a harmonic scalpel increases risk of biochemical leak but not postoperative pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: The effect of a harmonic scalpel on postoperative pancreatic fistula (POPF) has not been addressed. This study assessed the effect of pancreatic neck transection using a harmonic scalpel on rate and severity of POPF after pancreaticoduodenectomy (PD). METHODS: This retrospective analysis included patients who underwent PD at National Taiwan University Hospital between July 2015 and March 2019. We compared rate and severity of POPF between patients who underwent pancreatic neck transection using a harmonic scalpel versus electrosurgical unit. RESULTS: Of 422 consecutive PDs, the pancreatic neck was transected using a harmonic scalpel or electrosurgical unit in 144 and 278 patients, respectively. Use of a harmonic scalpel significantly increased risk of biochemical leak (25.7% versus [vs] 10.8%; P < 0.05) but not clinically relevant POPF (CR-POPF; 30.2% vs 26.4%; P = 0.41). Harmonic transection was an independent predictor of biochemical leak (odds ratio [OR] = 2.93; P < 0.05) but not CR-POPF (OR = 0.83; P = 0.41) or other major complications (OR = 0.72; P = 0.27). There was no significant intergroup difference in postoperative hospital stay. CONCLUSION: Pancreatic neck transection using a harmonic scalpel increased risk of biochemical leak but not CR-POPF or other major complications.