Nanosome-Mediated Delivery Of Hdac Inhibitors and Oxygen Molecules for the Transcriptional Reactivation of Latent Hiv-Infected Cd4+ T Cells.

The treatment of human immunodeficiency virus (HIV) infection is notoriously difficult due to the ability of this virus to remain latent in the host's CD4+ T cells. Histone deacetylases (HDACs) interfere with DNA transcription in HIV-infected hosts, resulting in viral latency. Therefore, HDAC inhibitors can be used to activate viral transcription in latently infected cells, after which the virus can be eliminated through a shock-and-kill strategy. Here, a drug delivery system is developed to effectively deliver HDAC inhibitors to latent HIV-infected cells. Given that the efficacy of HDAC inhibitors is reduced under hypoxic conditions, oxygen-containing nanosomes are used as drug carriers. Oxygen-containing nanosomes can improve the efficiency of chemotherapy by delivering essential oxygen to cells. Additionally, their phospholipid bilayer structure makes them uniquely well-suited for drug delivery. In this study, a novel drug delivery system is developed by taking advantage of the oxygen carriers in these oxygen nanosomes, incorporating a multi-drug strategy consisting of HDAC inhibitors and PKA activators, and introducing CXCR4 binding peptides to specifically target CD4+ T cells. Oxygen nanosomes with enhanced targeting capability through the introduction of the CXCR4 binding peptide mitigate drug toxicity and slow down drug release. The observed changes in the expression of p24, a capsid protein of HIV, indirectly confirm that the proposed drug delivery system can effectively induce transcriptional reactivation of HIV in latent HIV-infected cells.

Rare Case of Managing and Evaluating Viability after Replantation of a Serial Self-Amputated Bilateral Testis by a Patient with Schizophrenia: A Case Report.

Amputation of the testis is very rare in clinical situations; therefore, most surgeons have no experience with an amputated testis. In this case, a 31-year-old male with schizophrenia amputated both testes due to self-mutilation. We performed replantation surgery via microscopy. On postoperative day 1, he removed his right testis by using his hand, even though his hands were restrained. The second attack disrupted the viability of the right testis. However, after proper management, we checked the normal sex hormone level by preserving the replanted left testis. We evaluated the viability of the replanted testis by performing five examinations, namely, intraoperative indocyanine green injection, testicular scan with technetium pertechnetate, contrast-enhanced computerized tomography, Doppler ultrasonography, and serum testosterone level. In this report, we aimed to describe our rare experience about management with replantation of the amputated testes and evaluation of their viability.

Brugada Syndrome Unmasked by Cellulitis of the Face.

A 35-year-old male patient with no specific history visited an emergency medical center with a chief complaint of facial swelling accompanied by fever (38.3°C). Contrast-enhanced facial computed tomography confirmed diffuse soft tissue swelling and facial infiltration of inflammation. Additional laboratory findings revealed elevated white blood cell count and C-reactive protein level. The patient also complained of chest pain; therefore, electrocardiography was performed, which confirmed a curved pattern-like ST-segment elevation (≥2 mm) of V2 without elevated cardiac enzyme levels. Based on various test results, the patient was diagnosed with Brugada syndrome. He was administered intravenous empirical antibiotics and intravenous ibuprofen as an antipyretic for the treatment of facial cellulitis and Brugada syndrome. After the resolution of the symptoms, his body temperature normalized. A subsequent electrocardiogram confirmed a normal sinus rhythm pattern. This case report shows that Brugada syndrome, a rare but life-threatening disease, can be unmasked by facial cellulitis. Because antipyretics can immediately reduce the critical rate of sudden cardiac death, Brugada syndrome should be differentially diagnosed, with an evaluation of facial cellulitis, to prevent sudden cardiac death.

Trends in nano-platforms for the treatment of viral infectious diseases.

Viral diseases have always been a major health issue, from the currently eradicated poliovirus to the still unresolved human immunodeficiency virus, and have since become a recent global threat brought about by the COVID-19 pandemic. Pathogenic viruses easily spread through various means such as contaminated food and water intake, exchange of bodily fluids, or even inhalation of airborne particles mainly due to their miniscule size. Furthermore, viral coats contain virulent proteins which trigger assimilation into target cells on contact through either direct penetration or induction of endocytosis. In some viruses their outer envelope contains masking ligands that create a means of escape from detection of immune cells. To deal with the nanometer size range and biomolecular-based invasion mechanism, nanoparticles are highly suitable for the treatment. The review highlights the progress in nanoparticle technology, particularly viral therapeutics, including therapeutic strategies and existing clinical applications.

Verifying the Versatility and Reliability of Free Lateral Arm Flap for Head and Neck Reconstruction.

The lateral arm flap is an alternative to the conventional radial forearm flap and has been widely used due to advancements in flap characteristics. Especially, the fasciocutaneous flap has been widely used in head and neck reconstruction due to its versatile characteristics and surgical feasibility. This flap has successfully undergone several useful modifications based on various anatomical studies. Here, the authors aimed to verify the versatility and reliability of free lateral arm flap reconstruction of numerous head and neck defects. Twelve patients (6 men and 6 women; mean age, 66 years) with various types of lateral arm flaps from May 2017 to April 2019 were included. The anatomical reconstruction area was widely distributed across the facial subunits, tongue and oral cavity, and hypopharynx, among others. The flap varied in size from 3 × 5 cm to 17 × 7 cm, and the average pedicle length was 5.58 cm. The versatility of the lateral arm flap enabled successful coverage of various defects in all cases. Among 12 patients, the donor site outcome was rated as excellent and good by 2 and 10 patients, respectively. Three patients complained of post-operative hypoesthesia, which was subsequently resolved. The lateral arm flap is a unique and extremely versatile soft tissue free flap. Its versatility facilitates continuous modification of the flap and its application in various areas in different forms with excellent contour outcomes. The authors successfully verified the evolving methods and advantages of lateral arm flaps in the treatment of various head and neck defects.

Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition.

Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to ¼100 µM). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-κB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas.

Preventive Effect of Synthetic Tryptophan Metabolite on Silicone Breast Implant-Induced Capsule Formation.

BACKGROUND: In the field of plastic surgery, capsular contracture after silicone breast implant surgery is a major clinical problem. This experimental study confirms that the synthetic tryptophan metabolite N-(3',4'-dimethoxycinnamonyl) anthranilic acid (Tranilast) reduces capsule formation and prevents capsular contracture. METHODS: Eighteen New Zealand white rabbits were divided into 2 groups. In the experimental group, implants were inserted into each rabbit, and oral synthetic tryptophan metabolite was administered daily at a dose of 5 mg/kg in 10 mL of saline. In the control group, rabbits received implants and the same amount of saline without the metabolite. After 2 months, peri-implant tissues were harvested and analyzed. RESULTS: The thickness of the capsules and the inflammatory cell counts were decreased in the experimental group (P < 0.001). The collagen fibers in the experimental group were thinner, less dense, and more organized than in control group. The results of reverse transcription quantitative polymerase chain reaction analysis showed that the genes for transforming growth factor ß1 (P = 0.002), alpha smooth muscle actin (P < 0.001), and collagen types I (P = 0.002) and III (P = 0.004) were underexpressed in the experimental groups. Furthermore, the counts of T-cell immunity-related cytokine presenting cells were decreased in the experimental groups (CD3, 4, 25, 45RA, 45RO, 69, interleukin-2, 4 [P < 0.001], and interferon γ [P = 0.028]). CONCLUSIONS: This study confirms that a synthetic derivative of a tryptophan metabolite decreases capsule formation and prevents capsular contracture by inhibiting the differentiation of fibroblasts to myofibroblasts, selectively inhibiting collagen synthesis, and decreasing specific T-cell immune responses by changing anti-inflammatory cytokine expression.

Current Approaches Including Novel Nano/Microtechniques to Reduce Silicone Implant-Induced Contracture with Adverse Immune Responses.

Capsular contracture, which is the pathologic development of fibrous capsules around implants, is a major complication of reconstructive and aesthetic breast surgeries. Capsular contracture can cause implant failure with breast hardening, deformity, and severe pain. The exact mechanisms underlying this complication remain unclear. In addition, anaplastic large cell lymphoma is now widely recognized as a very rare disease associated with breast implants. Foreign body reactions are an inevitable common denominator of capsular contracture. A number of studies have focused on the associated immune responses and their regulation. The present article provides an overview of the currently available techniques, including novel nano/microtechniques, to reduce silicone implant-induced contracture and associated foreign body responses.

Restoration of miR-29b exerts anti-cancer effects on glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is known as one of the most fatal forms of cancer. MicroRNAs have been widely implicated in the regulation of mammalian development and pathogenesis. The brain-enriched miR-29 subfamilies are known to be exclusively expressed in the developing brain, and they are aberrantly down-regulated in GBM. This study aims to elucidate the role of miR-29b in GBM development and the feasibility of therapeutic targeting using conjugated nanoparticles. METHODS: After confirmation of miR-29b expression levels in GBM tissues by analysis of open source data, the anticancer effect of miR-29b was tested by the introduction of syn-hsa-miR-29b-3p in the A172 GBM cell line. In vitro studies of cell viability and apoptosis and ex vivo study using GBM tissue slice cultures from 3 patients and nanoparticle delivery of miR-29b were performed. RESULTS: We discovered an increase in apoptotic cell populations with the introduction of miR-29b in the GBM cell line. An established human-derived GBM tissue slice culture system confirmed the anticancer effect of miR-29b-conjugated nanoparticles. Using PCR array, we found that exogenous miR-29b inhibits the expression of COL1A2, COL3A1, COL4A1, ELN, ITGA11, MMP24, and SPARC, which mediates an anticancer effect. CONCLUSIONS: miR-29b may serve as a putative therapeutic molecule when its expression is restored using a nanoparticle delivery system in GBM.

Factors Associated with Clinical Outcomes in Patients with Primary Intraventricular Hemorrhage.

BACKGROUND Primary intraventricular hemorrhage (PIVH) is an uncommon type of intracerebral hemorrhage. Owing to its rarity, the clinical and radiological factors affecting outcomes in patients with PIVH have not been widely studied. MATERIAL AND METHODS We retrospectively reviewed 112 patients (mean age 53 years) treated for PIVH at our institution from January 2004 to December 2014. Clinical and radiological parameters were analyzed 3 months after initial presentation to identify factors associated with clinical outcomes, as assessed by the Glasgow Outcome Scale (favorable ≥4, unfavorable <4). RESULTS Of the 99 patients who underwent angiography, causative vascular abnormalities were found in 46%, and included Moyamoya disease, arteriovenous malformation, and cerebral aneurysm. At 3 months after initial presentation, 64% and 36% of patients were in the favorable and unfavorable outcome groups, respectively. The mortality rate was 19%. However, most survivors had no or mild deficits. Age, initial Glasgow Coma Scale (GCS) score, simplified acute physiology score (SAPS II), modified Graeb score, and various radiological parameters reflecting ventricular dilatation were significantly different between the groups. Specifically, a GCS score of less than 13 (p=0.015), a SAPS II score of less than 33 (p=0.039), and a dilated fourth ventricle (p=0.043) were demonstrated to be independent predictors of an unfavorable clinical outcome. CONCLUSIONS In this study we reveal independent predictors of poor outcome in primary intraventricular hemorrhage patients, and show that nearly half of the patients in our study had predisposing vascular abnormalities. Routine angiography is recommended in the evaluation of PIVH to identify potentially treatable etiologies, which may enhance long-term prognosis.

Reactive oxygen species production has a critical role in hypoxia-induced Stat3 activation and angiogenesis in human glioblastoma.

Glioblastoma is the most aggressive primary brain tumor with hypoxia-associated morphologic features including pseudopalisading necrosis and endothelial hyperplasia. It has been known that hypoxia can activate signal transducer and activator of transcription 3 (Stat3) and subsequently induce angiogenesis. However, the molecular mechanism underlying hypoxia-induced Stat3 activation has not been defined. In this study, we explored the possible implication of reactive oxygen species (ROS) in hypoxia-driven Stat3 activation in human glioblastoma. We found that hypoxic stress increased ROS production as well as Stat3 activation and that ROS inhibitors (diphenyleneiodonium, rotenone and myxothiazol) and an antioxidant (N-acetyl-L-cysteine) blocked Stat3 activation under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is involved in hypoxia-induced ROS production. Nox4 expression was found to be increased at both mRNA and protein levels in hypoxic glioblastoma cells. In addition, siRNA-mediated knockdown of Nox4 expression abolished hypoxia induced Stat3 activation and vascular endothelial growth factor expression, which is associated with tumor cells' ability to trigger tube formation of endothelial cells in vitro. Our findings indicate that elevated ROS production plays a crucial role for Stat3 activation and angiogenesis in hypoxic glioblastoma cells.

Expression of astrocyte elevated gene-1 (AEG-1) in human meningiomas and its roles in cell proliferation and survival.

Astrocyte elevated gene-1 (AEG-1) has recently been proposed to be involved in tumor development, invasion, and metastasis in several human cancers. However, the functional importance of AEG-1 expression in human meningioma has not been determined. We investigate the level of AEG-1 expression by quantitative reverse transcription PCR, immunohistochemistry analysis, and western blotting in various human meningioma tissues and cells. To determine the suppressive effect of AEG-1 on meningioma progression, we inhibited AEG-1 expression using small interfering RNA and examined cell proliferation, apoptosis, colony formation and tumorigenicity in a mouse xenograft model. AEG-1 expression was frequently elevated at both mRNA and protein levels in meningioma tumor tissues and in meningioma-derived cells as well. This elevation was more commonly observed in high-grade tumors than in benign ones. The knockdown of AEG-1 led to a decrease in overall cell proliferation, as well as anchorage-independent growth of malignant meningioma. In addition, apoptotic cell death occurred in AEG-1 depleted meningioma cells through p-Akt and Bcl-2 suppression. Furthermore, a mouse xenograft meningioma model showed that inhibition of AEG-1 expression significantly decreased tumor growth. Altogether, these data show that the elevation of AEG-1 contributes to the malignant progression of meningiomas, suggesting that AEG-1 could be a novel therapeutic target against human meningiomas.

Romo1 is associated with ROS production and cellular growth in human gliomas.

Romo1 is a mitochondrial protein whose elevated expression is commonly observed in various types of human cancers. However, the expression status of Romo1 and its implication in the pathogenesis of human glioblastoma (GBM) remain largely undefined. To understand the role of Romo1 in the progression of GBM, we explored its expression in a series of GBM tissues and cell lines and determined its effect on ROS production, cell proliferation, and tumor growth. Romo1 was frequently overexpressed at the mRNA level in both primary tumors and cell lines and its elevation was more commonly observed in high grade tumors versus low grade tumors. Romo1 expression was associated with ROS production and its knockdown led to a marked reduction of in vitro cellular growth and anchorage-independent growth of GBM. Consistently, Romo1 depletion induced a G2/M arrest of the cell cycle that was accompanied with accumulation of phospho-cdc2. Furthermore, a mouse xenograft assay revealed that Romo1 depletion significantly decreased tumor formation and growth. Therefore, our data demonstrate that Romo1 upregulation is a common event in human GBMs and contributes to the malignant tumor progression, suggesting that Romo1 could be a new therapeutic target for human GBM.

Prognostic Factors of Clinical Outcomes in Patients with Spontaneous Thalamic Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a well-known condition, but ICH restricted to the thalamus is less widely studied. We investigated the prognostic factors of thalamic ICHs. MATERIAL AND METHODS: Seventy patients from January 2009 to November 2014 were retrospectively reviewed. Patients who demonstrated spontaneous ICH primarily affecting the thalamus on initial brain computed tomography (CT) were enrolled. Patients were categorized into 2 groups based on their Glasgow Outcome Scale (GOS) scores. Various presumptive prognostic factors were analyzed to investigate relationships between various clinical characteristics and outcomes. RESULTS: Of the enrolled patients, 39 showed a GOS of 4-5, and were categorized as the good outcome group, while another 31 patients showed a GOS of 1-3 and were categorized as the poor outcome group. Initial GCS score, calculated volume of hematoma, presence of intraventricular hemorrhage (IVH), coexisting complications, hydrocephalus, performance of external ventricular drainage, and modified Graeb's scores of patients with IVH were significantly different between the 2 groups. In multivariate analysis, among the factors above, initial GCS score (P=0.002, Odds ratio [OR]=1.761, Confidence interval [CI]=1.223-2.536) and the existence of systemic complications (P=0.015, OR=0.059, CI=0.006-0.573) were independently associated with clinical outcomes. Calculated hematoma volume showed a borderline relationship with outcomes (P=0.079, OR=0.920, CI=0.839-1.010). CONCLUSIONS: Initial GCS score and the existence of systemic complications were strong predictive factors for prognosis of thalamic ICH. Calculated hematoma volume also had predictive value for clinical outcomes.

Immediate reconstruction of the maxillary sinus after resection of preoperatively misdiagnosed unicystic ameloblastoma with an ectopic third molar.

We report a case of unicystic ameloblastoma associated with an ectopic third molar in the right maxillary sinus, which was misdiagnosed as a dentigerous cyst on preoperative small incisional biopsy. Surgical enucleation of the cystic lesion was performed under general anesthesia with immediate reconstruction of the maxillary sinus using titanium mesh plate. The patient's postoperative recovery was uneventful, and there was no evidence of tumor recurrence during the 7-month follow-up period.

Forkhead box M1 is regulated by heat shock factor 1 and promotes glioma cells survival under heat shock stress.

The forkhead box M1 (FoxM1) is a key transcription factor regulating multiple aspects of cell biology. Prior studies have shown that FoxM1 is overexpressed in a variety of human tumors, including brain tumor, and plays a critical role in cancer development and progression. In this study we found that FoxM1 was up-regulated by heat shock factor 1 (HSF1) under heat shock stress condition in multiple cell lines. Knockdown of HSF1 with HSF1 siRNA or inhibition of HSF1 with a HSF1 inhibitor abrogated heat shock-induced expression of FoxM1. Genetic deletion of HSF1 in mouse embryo fibroblast cells also abolished heat shock stress-induced FoxM1 expression. Moreover, we showed that HSF1 directly bound to FoxM1 promoter and increased FoxM1 promoter activity. Furthermore, we demonstrated that FoxM1 was required for the G(2)-M phase progression through regulating Cdc2, Cdc20, and Cdc25B under a mild heat shock stress but enhanced cell survival under lethal heat shock stress condition. Finally, in human glioblastoma specimens, FoxM1 overexpression correlated with elevated HSF1 expression. Our results indicate that FoxM1 is regulated by HSF1 and is critical for HSF1-mediated heat shock response. We demonstrated a novel mechanism of stress resistance controlled by HSF1 and a new HSF-FoxM1 connection that mediates cellular thermotolerance.

Risk factors of delayed surgical evacuation for initially nonoperative acute subdural hematomas following mild head injury.

BACKGROUND: Although the majority of patients with minimal acute subdural hematomas (aSDHs) can be managed conservatively, some require delayed aSDH evacuation due to hematoma enlargement. This study was designed to determine the risk factors associated with delayed hematoma enlargement leading to surgery in patients with aSDHs who did not initially require surgical intervention. METHODS: From 2002 to 2012, 98 patients were treated for nonoperative aSDHs following mild head injury (Glasgow Coma Scale scores of 13-15). The outcome variables were radiographic evidence of SDH enlargement on serially obtained computed tomography (CT) images and later surgical evacuation. Univariate and multivariate analyses were applied to both the demographic and initial radiographic features to identify risk factors for SDH progression and surgery. RESULTS: Overall, 64 patients (65 %) revealed minimal SDH or spontaneous hematoma resolution (conservative group) with conservative management at their last follow-up CT scan. The remaining 34 patients (35 %) received delayed hematoma evacuation (delayed surgery group) a median of 17 days after the head trauma. There were no significant differences between the two groups for baseline characteristics, including age, injury type, degree of brain atrophy, prior history of antithrombotic drugs, and coagulopathy. The presence of cerebral contusions and subarachnoid hemorrhages was more common in the conservative group (p = 0.003 and p = 0.003, respectively). On multivariate analysis, hematoma volume (p = 0.01, odds ratio [OR] = 1.094, 95 % confidence interval [CI] = 1.021-1.173) and degree of midline shift (p = 0.01, OR = 1.433, 95 % CI = 1.088-1.888) on the initial CT scan were independently associated with delayed hematoma evacuation. CONCLUSIONS: A critical proportion of patients with minimal aSDHs occurring after mild head injury can progress over several weeks and require hematoma evacuation. Especially patients with a large initial SDH volume and accompanying midline shift require careful monitoring of hematoma progression.

Clear cell hidradenocarcinoma of the ear helix: report of primary ear helix adnexal carcinoma with regional lymph node metastasis.

Clear cell hidradenocarcinoma is a rare tumor of eccrine sweat gland origin that has a predilection for the head and neck. It has an indolent growth pattern and a higher incidence of regional and distant metastases. Metastasizing adnexal carcinomas are rare; thus, currently there is no uniform treatment guideline. We report a case of an 89-year-old female patient with clear cell hidradenocarcinoma manifesting in the right ear helix that metastasized to the right parotid gland who was treated by wide local excision and radiation therapy.