Strategies to Overcome Hurdles in Cancer Immunotherapy.

Despite marked advancements in cancer immunotherapy over the past few decades, there remains an urgent need to develop more effective treatments in humans. This review explores strategies to overcome hurdles in cancer immunotherapy, leveraging innovative technologies including multi-specific antibodies, chimeric antigen receptor (CAR) T cells, myeloid cells, cancer-associated fibroblasts, artificial intelligence (AI)-predicted neoantigens, autologous vaccines, and mRNA vaccines. These approaches aim to address the diverse facets and interactions of tumors' immune evasion mechanisms. Specifically, multi-specific antibodies and CAR T cells enhance interactions with tumor cells, bolstering immune responses to facilitate tumor infiltration and destruction. Modulation of myeloid cells and cancer-associated fibroblasts targets the tumor's immunosuppressive microenvironment, enhancing immunotherapy efficacy. AI-predicted neoantigens swiftly and accurately identify antigen targets, which can facilitate the development of personalized anticancer vaccines. Additionally, autologous and mRNA vaccines activate individuals' immune systems, fostering sustained immune responses against cancer neoantigens as therapeutic vaccines. Collectively, these strategies are expected to enhance efficacy of cancer immunotherapy, opening new horizons in anticancer treatment.

Magnetically Actuated Trigger Transient Soft Actuators Comprising On-Demand Photo-Initiated and Thermo-Degradable Polypropylene Carbonate-Photo-Acid Generator.

Lifetime-reconfigurable soft robots have emerged as a new class of robots, emphasizing the unmet needs of futuristic sustainability and security. Trigger-transient materials that can both actuate and degrade on-demand are crucial for achieving life-reconfigurable soft robots. Here, we propose the use of transient and magnetically actuating materials that can decompose under ultraviolet light and heat, achieved by adding photo-acid generator (PAG) and magnetic particles (Sr-ferrite) to poly(propylene carbonate) (PPC). Chemical and thermal analyses reveal that the mechanism of PPC-PAG decomposition occurs through PPC backbone cleavage by the photo-induced acid. The self-assembled monolayer (SAM) encapsulation of Sr-ferrite preventing the interaction with the PAG allowed the transience of magnetic soft actuators. We demonstrate remotely controllable and degradable magnetic soft kirigami actuators using blocks with various magnetized directions. This study proposes novel approaches for fabricating lifetime-configurable magnetic soft actuators applicable to diverse environments and applications, such as enclosed/sealed spaces and security/military devices.

Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability.

Microsatellite instability (MSI) is a hypermutable condition caused by DNA mismatch repair system defects, contributing to the development of various cancer types. Recent research has identified Werner syndrome ATP-dependent helicase (WRN) as a promising synthetic lethal target for MSI cancers. Herein, we report the first discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for MSI cancer therapy. Initial computational analysis and biological evaluation identified a new scaffold for a WRN inhibitor. Subsequent SAR study led to the discovery of a highly potent WRN inhibitor. Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.

Electroceuticals for Regeneration of Long Nerve Gap Using Biodegradable Conductive Conduits and Implantable Wireless Stimulator.

Regeneration of over 10 mm long peripheral nerve defects remains a challenge due to the failure of regeneration by prolonged axotomy and denervation occurring in long-term recovery. Recent studies reveal that conductive conduits and electrical stimulation accelerate the regeneration of long nerve defects. In this study, an electroceutical platform combining a fully biodegradable conductive nerve conduit and a wireless electrical stimulator is proposed to maximize the therapeutic effect on nerve regeneration. Fully biodegradable nerve conduit fabricated using molybdenum (Mo) microparticles and polycaprolactone (PCL) can eliminate the unwanted effects of non-degradable implants, which occupy nerve paths and need to be removed through surgery increasing the risk of complications. The electrical and mechanical properties of Mo/PCL conduits are optimized by controlling the amounts of Mo and tetraglycol lubricant. The dissolution behavior and electrical conductivity of biodegradable nerve conduits in the biomimetic solutions are also evaluated. In in vivo experiments, the integrated strategy of a conductive Mo/PCL conduit with controlled therapeutic electrical stimulation shows accelerated axon regeneration for long sciatic nerve defects in rats compared to the use of the Mo/PCL conduit without stimulation and has a significant therapeutic effect based on the results obtained from the functional recovery test.

Case report: Non-thrombotic iliac vein lesion: an unusual cause of unilateral leg swelling in a patient with endometrial carcinoma.

81-year-old female presented with subacute right lower extremity edema due to iliac vein compression by a markedly enlarged external iliac lymph node later identified as newly relapsed metastatic endometrial carcinoma. The patient underwent a full evaluation of the iliac vein lesion and cancer and had an intravenous stent placed with complete resolution of symptoms post-procedure.

Economic burden of brain metastases in non-small cell lung cancer patients in South Korea: A retrospective cohort study using nationwide claims data.

Brain metastases (BM) are common in patients with non-small cell lung cancer (NSCLC). However, the pure economic burden of BM is unknown. This study aimed to evaluate the impact of BM on healthcare costs and resource utilization in patients with NSCLC by comparing patients with and without BM. This was a retrospective cohort analysis of South Korean health insurance review and assessment claims data. Patients with stage IIIB or IV NSCLC were identified (March 1, 2013 to February 28, 2018). We compared their two-year and per-patient-per-month (PPPM) healthcare costs and resource utilization with 1:3 propensity score-matched patients without the condition. A generalized linear model was used to estimate the impact of BM and other covariates on healthcare costs. After propensity score matching with the 33 402 newly diagnosed cases of stage IIIB or IV NSCLC, 3435 and 10 305 patients were classified as having or not having BM, respectively. Mean healthcare costs were significantly greater in patients with BM for both the two years (US$ 44 692 vs. US$ 32 230, p < .0001) and PPPM (US$ 3510 vs. US$ 2573, p < .0001). The length of hospital stay was longer in patients with BM (79.15 vs. 69.41 days for two years, p < .0001; 7.69 vs. 6.86 days PPPM, p < .0001), and patients with BM had more outpatient visits (50.61 vs. 46.43 times for two years, p < .0001; 3.64 vs. 3.40 times PPPM costs, p < .0001). The costs of drugs, radiology/radiotherapy, and admission comprised the majority of PPPM costs and were higher in patients with BM. The generalized linear model analysis suggested that patients with BM had significantly increased healthcare costs (by 1.29-fold, 95% confidence interval 1.26-1.32). BM is a significant economic burden for patients with NSCLC. Therefore, it is important to prevent BM in patients with NSCLC to reduce their economic burden.

Readout Integrated Circuit for Small-Sized and Low-Power Gas Sensor Based on HEMT Device.

This paper presents a small-sized, low-power gas sensor system combining a high-electron-mobility transistor (HEMT) device and readout integrated circuit (ROIC). Using a semiconductor-based HEMT as a gas-sensing device, it is possible to secure high sensitivity, reduced complexity, low power, and small size of the ROIC sensor system. Unlike existing gas sensors comprising only HEMT elements, the proposed sensor system has both an ROIC and a digital controller and can control sensor operation through a simple calibration process with digital signal processing while maintaining constant performance despite variations. The ROIC mainly consists of a transimpedance amplifier (TIA), a negative-voltage generator, and an analog-to-digital converter (ADC) and is designed to match a minimum target detection unit of 1 ppm for hydrogen. The prototype ROIC for the HEMT presented herein was implemented in a 0.18 µm complementary metal-oxide-semiconductor (CMOS) process. The total measured power consumption and detection unit of the proposed ROIC for hydrogen gas were 3.1 mW and 2.6 ppm, respectively.

A Case of Isolated External Iliac Vein Compression Syndrome and the Role of Advanced Imaging.

Isolated external iliac vein compression syndrome is an uncommon cause of nonthrombotic venous stenosis that causes chronic venous hypertension leading to painful swelling, skin discoloration, and ulcer formation. We present a case of an 86-year old man with refractory lower extremity edema for several years who had been treated with diuretics and antibiotics without relief of symptoms. With the help of invasive and noninvasive imaging modalities, we were able to diagnose and manage isolated nonthrombotic left external iliac vein stenosis as a result of ipsilateral external iliac artery compression.

Cumulative directional calcium gluing between phosphate and silicate: A facile, robust and biocompatible strategy for siRNA delivery by amine-free non-positive vector.

For siRNA therapeutics, the use of positively charged amine-rich delivery vectors has been indispensable, but the amine-associated toxicological responses remain a clinical conundrum. Herein, we report a new strategy of harnessing a biocompatible, biodegradable and well-tolerated nanomaterial as an amine-free non-positive carrier for siRNA delivery. By employing mesoporous silica nanoparticles (MSNs) as a biocompatible vector, siRNA is loaded nonconventionally through calcium ion (Ca2+)-mediated interconnection (calcium gluing) between phosphates of siRNA and surface silicates of MSNs in a sequential, cumulative and directional way. The "one-pot" gluing process utilizing endogenously abundant Ca2+ ions offers a simple but robust means of siRNA loading on the non-positive bare surface of MSNs without the aid of multi-amine functionalization, and thus minimizes the risk of amine-associated cytotoxicity and immunogenicity while keeping the intrinsic biocompatibility of MSNs. As demonstrated with loading of an anticancer siRNA, this strategy allows stable in vivo delivery of siRNA for targeted gene silencing, and capitalizes on the unique structural versatility of MSNs by simultaneously delivering a pore-loaded chemodrug to synergistically enhance the treatment efficacy. Therefore, the Ca2+-glued MSNs as a general siRNA carrier platform provide a less toxic, less laborious and more utilitarian delivery tool for more effective and safer siRNA therapeutics.

Late-Onset Nonthrombotic Left Common Iliac Vein Compression Secondary to Degenerative Lumbar Disc: A Case Report of May-Thurner Variant.

May-Thurner syndrome (MTS) refers to venous outflow obstruction caused by extrinsic compression of the left common iliac vein (LCIV) by the overlying pulsatile right common iliac artery against lumbar vertebrae. The classic clinical presentation is acute unilateral left leg painful swelling due to deep venous thrombosis in a young woman in the second or third decade of life. We present a case of a 66-year-old woman who presented with late-onset left leg swelling caused by nonthrombotic venous hypertension due to degenerative lumbar disc bulge leading to LCIV compression against the left common iliac artery which was confirmed by computed tomography and intravascular ultrasound. Our case highlights the importance of high index of suspicion for MTS in elderly patients with unilateral leg swelling and the importance of multimodality imaging for understanding the mechanism and appropriate treatment of MTS.

Stenosis Caused by Suture-Mediated Vascular Closure Device in an Angiographic Normal Common Femoral Artery: Its Mechanism and Management.

Vascular closing devices (VCDs) are widely used to replace manual compression at the femoral puncture site and to reduce the discomfort of patients undergoing percutaneous coronary procedure by shortening bed rest. Among the vascular complications related to these devices, the femoral artery stenosis or occlusion is rarely reported, and its standard management is not well established. We report a case of symptomatic femoral artery stenosis caused by suture-mediated VCD and managed using rotational atherectomy device and balloon angioplasty. In addition, we propose the possible mechanisms for this complication.

Comparison of manual compression and vascular hemostasis devices after coronary angiography or percutaneous coronary intervention through femoral artery access: A meta-analysis of randomized controlled trials.

OBJECTIVES: To compare the efficacy and safety of manual compression (MC) with vascular hemostasis devices (VHD) in patients undergoing coronary angiography (CA) or percutaneous coronary intervention (PCI) through femoral artery access. INTRODUCTION: The use of femoral artery access for coronary procedures may result in access-related complications, prolonged immobility and discomfort for the patients. MC results in longer time-to-hemostasis (TTH) and time-to-ambulation (TTA) compared to VHDs but its role in access-related complications remains unclear in patients undergoing coronary procedures. METHODS: We searched MEDLINE, EMBASE, Cochrane CENTRAL and relevant references for English language randomized controlled trials (RCT) from inception through September 30, 2016. We performed the meta-analysis using random effects model. The outcomes were time-to-hemostasis, time-to-ambulation, major bleeding, large hematoma >5cm, pseudoaneurysm and other adverse events. RESULTS: The electronic database search resulted in a total of 44 RCTs with a total of 18,802 patients for analysis. MC, compared to VHD resulted in longer TTH [mean difference (MD): 11.21min; 95% confidence interval (CI) 8.13-14.29; P<0.00001] and TTA [standardized mean difference: 1.2 (0.79-1.62); P<0.00001] along with excess risk of hematoma >5cm formation [risk ratio (RR): 1.38 (1.15-1.67); P=0.0008]. MC resulted in similar risk of major bleeding [1.01 (0.64-1.60); P=0.95] pseudoaneurysm [0.99 (0.75-1.29); P=0.92], infections [0.52 (0.25-1.10); P=0.09], need of surgery [0.60 (0.29-1.22); P=0.16), AV fistula [0.93 (0.68-1.27); P=0.63] and ipsilateral leg ischemia [0.95 (0.57-1.60); P=0.86] compared to VHD. CONCLUSION: Manual compression increase time-to-hemostasis, time-to-ambulation and risk of hematoma formation compared vascular hemostasis devices.

Different Sequences of Fractionated Low-Dose Proton and Single Iron-Radiation-Induced Divergent Biological Responses in the Heart.

Deep-space travel presents risks of exposure to ionizing radiation composed of a spectrum of low-fluence protons (1H) and high-charge and energy (HZE) iron nuclei (e.g., 56Fe). When exposed to galactic cosmic rays, each cell in the body may be traversed by 1H every 3-4 days and HZE nuclei every 3-4 months. The effects of low-dose sequential fractionated 1H or HZE on the heart are unknown. In this animal model of simulated ionizing radiation, middle-aged (8-9 months old) male C57BL/6NT mice were exposed to radiation as follows: group 1, nonirradiated controls; group 2, three fractionated doses of 17 cGy 1H every other day (1H × 3); group 3, three fractionated doses of 17 cGy 1H every other day followed by a single low dose of 15 cGy 56Fe two days after the final 1H dose (1H × 3 + 56Fe); and group 4, a single low dose of 15 cGy 56Fe followed (after 2 days) by three fractionated doses of 17 cGy 1H every other day (56Fe + 1H × 3). A subgroup of mice from each group underwent myocardial infarction (MI) surgery at 28 days postirradiation. Cardiac structure and function were assessed in all animals at days 7, 14 and 28 after MI surgery was performed. Compared to the control animals, the treatments that groups 2 and 3 received did not induce negative effects on cardiac function or structure. However, compared to all other groups, the animals in group 4, showed depressed left ventricular (LV) functions at 1 month with concomitant enhancement in cardiac fibrosis and induction of cardiac hypertrophy signaling at 3 months. In the irradiated and MI surgery groups compared to the control group, the treatments received by groups 2 and 4 did not induce negative effects at 1 month postirradiation and MI surgery. However, in group 3 after MI surgery, there was a 24% increase in mortality, significant decreases in LV function and a 35% increase in post-infarction size. These changes were associated with significant decreases in the angiogenic and cell survival signaling pathways. These data suggest that fractionated doses of radiation induces cellular and molecular changes that result in depressed heart functions both under basal conditions and particularly after myocardial infarction.

A new test for diagnosing vasovagal syncope: Standing after treadmill test with sublingual nitrate administration.

INTRODUCTION: Increased adrenergic tone might be an additional trigger of orthostatic stress of vasovagal syncope (VVS). Exercise before standing might provide increased sensitivity compared to standing using a sublingual nitroglycerines protocol during tilt table testing. The aim of this study was to evaluate the diagnostic value of treadmill testing before standing with nitroglycerin administration. METHODS AND RESULTS: A total of 36 patients with syncope or presyncope were enrolled for the test. VVS was confirmed in 29 patients according to the Calgary Score (≥ -2), including 20 patients who were likely to have typical (classical) VVS. All 36 subjects were subjected to a novel provocation test consisting of treadmill test using the Bruce protocol followed by standing with administration of 300 µg sublingual nitroglycerin. Consequently, syncope or presyncope occurred in 22 patients of the 36 patients. The sensitivity and a specificity of the test for Calgary score based VVS was 82.7% and 85.75%, respectively. Reproducibility rate for typical VVS was 90% (18 of 20). In all symptomatic patients, systolic blood pressure dropped to < 90 mmHg and symptom occurred a mean of 6.7 ± 2.3 minutes after the nitroglycerine administration. No patient required anticholinergics injection to restore vital signs. CONCLUSIONS: Treadmill test with administration of sublingual nitroglycerines might be safely used to reproduce syncope in patients with VVS. More clinical experience and confirmation are needed to validate this protocol.

Giant coronary aneurysm management with Viabahn covered stent.

A 68year old female patient underwent coronary artery bypass surgery (CABG) 1year previously. At that time she had a giant coronary artery aneurysm (CAA) of the proximal right coronary artery and severe 3 vessel disease including a severe ostial right coronary artery stenosis, severe stenosis of the proximal and mid left anterior descending artery (LAD) and a totally occluded left circumflex artery. She underwent CABG including left internal mammary artery to LAD, aorto-saphenous venous graft (ASVG) to posterior descending artery and ASVG sequential to the first diagonal and obtuse marginal branch. Subsequent computed tomography and invasive angiography demonstrated increasing size of the aneurysm (from 42 by 37mm to 50 by 42mm) which was now fed retrograde via the graft to the posterior descending artery in addition to being fed antegrade by the native vessel through a high grade stenosis. Percutaneous covered stent insertion was planned. The aneurysm was traversed with a guide wire, but passage of Viabahn covered stents was difficult due to the 8 Fr guide catheter and the bulky and rigid structure of the Viabahn stent. Using a distal anchoring technique and dual guide catheters, successful passage of two Viabahn stents (two of 5 by 50mm) was accomplished. The technique utilized is described.

Finding multiple reaction pathways via global optimization of action.

Global searching for reaction pathways is a long-standing challenge in computational chemistry and biology. Most existing approaches perform only local searches due to computational complexity. Here we present a computational approach, Action-CSA, to find multiple diverse reaction pathways connecting fixed initial and final states through global optimization of the Onsager-Machlup action using the conformational space annealing (CSA) method. Action-CSA successfully overcomes large energy barriers via crossovers and mutations of pathways and finds all possible pathways of small systems without initial guesses on pathways. The rank order and the transition time distribution of multiple pathways are in good agreement with those of long Langevin dynamics simulations. The lowest action folding pathway of FSD-1 is consistent with recent experiments. The results show that Action-CSA is an efficient and robust computational approach to study the multiple pathways of complex reactions and large-scale conformational changes.

Percutaneous coronary intervention vs coronary artery bypass grafting for left main coronary artery disease? A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: It is not clear whether percutaneous coronary intervention (PCI) is as effective and safe as coronary artery bypass grafting (CABG) for left main coronary artery disease. We aimed to perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) that compared PCI and CABG in left main coronary disease. METHODS: We searched PubMed, EMBASE, Cochrane, Scopus and relevant references for RCTs (inception through, November 20, 2016 without language restrictions) and performed meta-analysis using random-effects model. All-cause mortality, myocardial infarction, revascularization rate, stroke, and major adverse cardiac and cerebrovascular events (MACCE) were the measured outcomes. RESULTS: Six RCTs with a total population of 4700 were analyzed. There was no difference in all-cause mortality at 30-day, one-year, and five-year (1.8% vs 1.1%; OR 0.60; 95% CI: 0.26-1.39; P=.23; I2 =9%) follow-up between PCI and CABG. CABG group had less myocardial infarction (MI) at five-year follow-up than PCI (5% vs 2.5%; OR 2.04; CI: 1.30-3.19; P=.002; I2 =1%). Revascularization rate favored CABG in one-year (8.6% vs 4.5%; OR 2; CI: 1.46-2.73; P<.0001; I2 =45%) and five-year (15.9% vs 9.9%; OR 1.73; CI: 1.36-2.20; P<.0001; I2 =0%) follow-up. Although stroke rate was lower in PCI group at 1 year, there was no difference in longer follow-up. MACCE at 5 years favored CABG (24% vs 18%; OR 1.45; CI: 1.19-1.76; P=.0001; I2 =0%). On subgroup analysis, MACCE were not different between two groups in low-to-intermediate SYNTAX group while it was higher for PCI group with high SYNTAX group. CONCLUSION: Percutaneous coronary intervention could be as safe and effective as CABG in a select group of left main coronary artery disease patients.