Gold nanoparticle delivery to solid tumors: a multiparametric study on particle size and the tumor microenvironment.

Nanoparticle (NP) delivery to solid tumors remains an actively studied field, where several recent studies have shed new insights into the underlying mechanisms and the still overall poor efficacy. In the present study, Au NPs of different sizes were used as model systems to address this topic, where delivery of the systemically administered NPs to the tumor as a whole or to tumor cells specifically was examined in view of a broad range of tumor-associated parameters. Using non-invasive imaging combined with histology, immunohistochemistry, single-cell spatial RNA expression and image-based single cell cytometry revealed a size-dependent complex interaction of multiple parameters that promoted tumor and tumor-cell specific NP delivery. Interestingly, the data show that most NPs are sequestered by tumor-associated macrophages and cancer-associated fibroblasts, while only few NPs reach the actual tumor cells. While perfusion is important, leaky blood vessels were found not to promote NP delivery, but rather that delivery efficacy correlated with the maturity level of tumor-associated blood vessels. In line with recent studies, we found that the presence of specialized endothelial cells, expressing high levels of CD276 and Plvap promoted both tumor delivery and tumor cell-specific delivery of NPs. This study identifies several parameters that can be used to determine the suitability of NP delivery to the tumor region or to tumor cells specifically, and enables personalized approaches for maximal delivery of nanoformulations to the targeted tumor.

Biotechnological applications of mammalian odorant-binding proteins.

The olfactory system of mammals allows the detection and discrimination of thousands of odors from the environment. In mammals, odorant-binding proteins (OBPs) are considered responsible to carry odorant molecules across the aqueous nasal mucus to the olfactory receptors (ORs). The three-dimensional structure of these proteins presents eight antiparallel ß-sheets and a short α-helical segment close to the C terminus, typical of the lipocalins family. The great ability of OBPs to bind differentiated ligand molecules has driven the research to understand the mechanisms underlying the OBP function in nature and the development of advanced biotechnological applications. This review describes the role of mammalian OBPs in the olfactory perception, highlighting the influence of several key parameters (amino acids, temperature, ionic strength, and pH) in the formation of the OBP/ligand complex. The information from the literature regarding OBP structure, affinity, the strength of binding, and stability inspiring the development of several applications herein detailed.

Reversible water driven chirality inversion in cellulose-based helices isolated from Erodium awns.

Among the movements observed in some cellulosic structures produced by plants are those that involve the dispersion and burial of seeds, as for example in Erodium from the Geraniaceae plant family. Here we report on a simple and efficient strategy to isolate and tune cellulose-based hygroscopic responsive materials from Erodium awns' dead tissues. The stimuli-responsive material isolated forms left-handed (L) or right-handed (R) helical birefringent transparent ribbons in the wet state that reversibly change to R helices when the material dries. The humidity-driven motion of dead tissues is most likely due to a composite material made of cellulose networks of fibrils imprinted by the plant at the nanoscale, which reinforces a soft wall polysaccharide matrix. The inversion of the handedness is explained using computational simulations considering filaments that contract and expand asymmetrically. The awns of Erodium are known to present hygroscopic movements, forming R helices in the dry state, but the possibility of actuating chirality via humidity suggests that these cellulose-based skeletons, which do not require complicated lithography and intricate deposition techniques, provide a diverse range of applications from intelligent textiles to micro-machines.

Genomic and transcriptomic analysis of Saccharomyces cerevisiae isolates with focus in succinic acid production.

Succinic acid is a platform chemical that plays an important role as precursor for the synthesis of many valuable bio-based chemicals. Its microbial production from renewable resources has seen great developments, specially exploring the use of yeasts to overcome the limitations of using bacteria. The objective of the present work was to screen for succinate-producing isolates, using a yeast collection with different origins and characteristics. Four strains were chosen, two as promising succinic acid producers, in comparison with two low producers. Genome of these isolates was analysed, and differences were found mainly in genes SDH1, SDH3, MDH1 and the transcription factor HAP4, regarding the number of single nucleotide polymorphisms and the gene copy-number profile. Real-time PCR was used to study gene expression of 10 selected genes involved in the metabolic pathway of succinic acid production. Results show that for the non-producing strain, higher expression of genes SDH1, SDH2, ADH1, ADH3, IDH1 and HAP4 was detected, together with lower expression of ADR1 transcription factor, in comparison with the best producer strain. This is the first study showing the capacity of natural yeast isolates to produce high amounts of succinic acid, together with the understanding of the key factors associated, giving clues for strain improvement.

Lower Extremity Fibro-Adipose Vascular Anomaly: A Post-surgical Rehabilitation Treatment.

Fibro-adipose vascular anomaly (FAVA) presents diagnostic and therapeutic challenges due to its rarity and overlapping features with other vascular malformations. Predominantly affecting the lower extremities, it manifests with pain and contracture, and surgical resection may be necessary in symptomatic cases. We present a case of a 36-year-old patient with FAVA in the right lower extremity, experiencing persistent symptoms since adolescence. The condition was managed with surgical gastrocnemius resection. Following surgery, the patient underwent a comprehensive rehabilitation program, resulting in significant clinical and functional improvement. This case highlights the importance of tailored interventions in FAVA. The challenges encountered in diagnosing and managing FAVA underscore the necessity for continued research and clinical discourse to improve patient care. Our report emphasizes the significance of collaborative and multidisciplinary care in maximizing functional recovery and quality of life post-gastrocnemius resection, highlighting the importance of optimized rehabilitation programs.

Nanomaterial-Mediated Delivery of MLKL Plasmids Sensitizes Tumors to Immunotherapy and Reduces Metastases.

Cancer immunotherapy has emerged as a promising approach for the induction of an antitumor response. While immunotherapy response rates are very high in some cancers, the efficacy against solid tumors remains limited caused by the presence of an immunosuppressive tumor microenvironment. Induction of immunogenic cell death (ICD) in the tumor can be used to boost immunotherapy response in solid cancers by eliciting the release of immune-stimulatory components. However, the delivery of components inducing ICD to tumor sites remains a challenge. Here, a novel delivery method is described for antitumor therapy based on MLKL (Mixed Lineage Kinase Domain-Like), a key mediator of necroptosis and inducer of ICD. A novel highly branched poly (ß-amino ester)s (HPAEs) system is designed to efficiently deliver MLKL plasmid DNA to the tumor with consequent enhancement of immune antigen presentation for T cell responses in vitro, and improved antitumor response and prolonged survival in tumor-bearing mice. Combination of the therapy with anti-PD-1 treatment revealed significant changes in the composition of the tumor microenvironment, including increased infiltration of CD8+ T cells and tumor-associated lymphocytes. Overall, the HPAEs delivery system can enhance MLKL-based cancer immunotherapy and promote antitumor immune responses, providing a potential treatment to boost cancer immunotherapies.

Influence of the Preparation Method on the Structural, Morphological and Dielectric Properties of FeNbO4 Ceramics.

In this work, iron niobate (FeNbO4) was prepared via two processes based on the sol-gel method: colloidal gel and polymeric gel. The obtained powders were submitted to heat treatments at different temperatures based on the results obtained via differential thermal analysis. The structures of the prepared samples were characterized via X-ray diffraction and the morphology was characterized via scanning electron microscopy. The dielectric measurements were performed in the radiofrequency region using the impedance spectroscopy technique and in the microwave range using the resonant cavity method. The influence of the preparation method was noticeable in the structural, morphological and dielectric properties of the studied samples. The polymeric gel method promoted the formation of monoclinic and orthorhombic iron niobate at lower temperatures. The differences in the samples' morphology were also remarkable, both in the size and shape of the grains. The dielectric characterization revealed that the dielectric constant and the dielectric losses had the same order of magnitude and similar trends. A relaxation mechanism was identified in all the samples.

Hemophagocytic Lymphohistiocytosis Secondary to Chronic Lymphocytic Leukemia Progression.

Hemophagocytic lymphohistiocytosis (HLH) is an acute, rare systemic hyperinflammatory disorder caused by a dysregulated immune cell function and massive cytokine release, often leading to multiple organ involvement and failure. Fever, hepatosplenomegaly, cytopenia, elevated liver enzymes, hypertriglyceridemia, and hyperferritinemia are the hallmarks of the disease. Its primary (genetic) form is typically observed in pediatric patients and its secondary, acquired form is seen in adult patients with an underlying autoimmune, malignant, or infectious disease. It is not frequently reported in patients with chronic lymphocytic leukemia (CLL) without an infectious or pharmacological trigger. We present a case of a 71-year-old patient with hemophagocytic lymphohistiocytosis due to the progression of chronic lymphocytic leukemia.

Splenic Infarction: A Rare Complication of Infectious Mononucleosis.

Infectious mononucleosis (IM) is caused by Epstein-Barr virus (EBV), and the condition is characterized by sore throat, fever, lymphadenopathy, and atypical lymphocytosis. These infections are common in early childhood, with a second peak occurring in late adolescence. EBV is spread by contact with oral secretions. Most cases of IM are self-limited. However, there are associated complications, some of which can be serious and fatal. We report the case of a 20-year-old man with splenic infarction and exuberant peritonsillar abscess secondary to an EBV infection. This case highlights the importance of accurate diagnoses and frequent monitoring in IM patients, given the risk of airway obstruction.

Kala-Azar: A Case Report.

Leishmaniasis is a zoonosis caused by unicellular protozoans Leishmania. The transmission can be zoonotic or anthroponotic, depending on the species, and the main vector is the phlebotomine sandfly. The disease is endemic in the tropics of Asia and Africa but is considered rare in Portugal, especially in immunocompetent hosts. Its main clinical syndromes constitute cutaneous leishmaniasis, mucocutaneous disease, and visceral leishmaniasis. The latter is also known as kala-azar and is caused by the infection of the phagocytes of the reticuloendothelial system, causing the typical symptoms: fever, hepatosplenomegaly, and pancytopenia. The clinical manifestations are non-specific, frequently causing a delay in the diagnosis, especially in nonendemic areas and immunocompetent hosts. Early diagnosis and treatment are essential, given the high mortality rate in untreated patients. The diagnosis is based on the direct visualization of the protozoan and molecular methods, such as polymerase chain reaction tests. Amphotericin B is considered the first-line treatment. We present a case of visceral leishmaniasis in an immunocompetent patient with fever, hepatosplenomegaly, and pancytopenia.

The Efficacy of Nanoparticle Delivery to Hypoxic Solid Tumors by ciRGD Co-Administration Depends on Neuropilin-1 and Neutrophil Levels.

The ability to improve nanoparticle delivery to solid tumors is an actively studied domain, where various mechanisms are looked into. In previous work, the authors have looked into nanoparticle size, tumor vessel normalization, and disintegration, and here it is aimed to continue this work by performing an in-depth mechanistic study on the use of ciRGD peptide co-administration. Using a multiparametric approach, it is observed that ciRGD can improve nanoparticle delivery to the tumor itself, but also to tumor cells specifically better than vessel normalization strategies. The effect depends on the level of tumor perfusion, hypoxia, neutrophil levels, and vessel permeability. This work shows that upon characterizing tumors for these parameters, conditions can be selected that can optimally benefit from ciRGD co-administration as a means to improve NP delivery to solid tumors.

Genetically encoded barcodes for correlative volume electron microscopy.

While genetically encoded reporters are common for fluorescence microscopy, equivalent multiplexable gene reporters for electron microscopy (EM) are still scarce. Here, by installing a variable number of fixation-stable metal-interacting moieties in the lumen of encapsulin nanocompartments of different sizes, we developed a suite of spherically symmetric and concentric barcodes (EMcapsulins) that are readable by standard EM techniques. Six classes of EMcapsulins could be automatically segmented and differentiated. The coding capacity was further increased by arranging several EMcapsulins into distinct patterns via a set of rigid spacers of variable length. Fluorescent EMcapsulins were expressed to monitor subcellular structures in light and EM. Neuronal expression in Drosophila and mouse brains enabled the automatic identification of genetically defined cells in EM. EMcapsulins are compatible with transmission EM, scanning EM and focused ion beam scanning EM. The expandable palette of genetically controlled EM-readable barcodes can augment anatomical EM images with multiplexed gene expression maps.

Ultrasound-Guided Injection of a Tendon-Compatible Hyaluronic Acid Preparation for the Management of Partial Thickness Rotator Cuff Tear: A Case Report.

Partial-thickness rotator cuff (RC) tear constitutes the most common cause of shoulder pain and disability. Its management is challenging, and a conservative approach is suggested as a first-line treatment. Nonetheless, minimally invasive approaches have been described in clinical trials, such as ultrasound (US)-guided tendon-compatible hyaluronic acid (HA) injection preparation in the rupture site. HA is believed to fill the intradermal space and thus support the regeneration process by its integration in the damaged extracellular matrix. A reduced healing period required for a tendon tear when treated with a tendon-compatible HA preparation compared to placebo has been previously described in the literature, enabling a more rapid return to exercise. The current study aims to provide a thorough analysis of a regular CrossFit practitioner case with a partial-thickness bursal-side RC tear of the anterior Supraspinatus (SS) fibers with 7 mm on the anteroposterior axis and 5 mm on the longitudinal axis in magnetic resonance imaging (MRI), that caused pain, and limited functional status. Two US-guided injections of a specific high molecular weight (one million Daltons) tendon-compatible HA preparation (12 mg/1.2 mL) separated by six weeks were performed. A supervised rehabilitation protocol was then followed and training was progressively introduced. In the 12 weeks follow-up visits, a reduction in pain intensity was noticed as well as an improvement of the functional status. At the six months, one year, and two years follow-ups, no pain and a normal joint function were observed, despite engaging in continuous overload and overhead activities during CrossFit practice. MRI was performed one year after the intervention presenting a reduction of the injury size and only a partial intrasubstance tear of 4 mm was observed in the SS tendon. US imaging in the two years follow-up presented an additional reduction in tear size to 3.9 mm length. No adverse effects were reported. It is thus believed that US-guided injections of tendon-compatible HA on partial-thickness RC tears can be a feasible and effective treatment option in the management of this frequent pathology, and more studies, particularly randomized controlled trials, should be implemented to substantiate and validate this approach.

Quincke's Disease Presenting After Cocaine Exposure.

Quincke's disease is a very rare form of upper airway angioedema, and it is characterized by a well-localized edematous reaction. Its epidemiology is not documented due to the rarity of this condition. Causes include allergic reactions, infectious diseases, and trauma, among others.  This article describes a rare case of a 27-year-old man who presented to the Emergency Department with isolated uvular edema associated with cocaine exposure.

A Rare Case of Sarcoidosis With Urologic Symptoms As the Presenting Feature.

Sarcoidosis is a multisystem idiopathic disease that can affect virtually any organ of the human body. However, genitourinary tract involvement is rare. We describe the case of a 33-year-old man with post-coital right scrotal pain. Scrotal ultrasound showed two vascularized nodular lesions in the right testicle and one in the left. A thoracic and abdominopelvic computed tomography scan showed micronodular infiltrate in the liver, spleen, lungs, and millimetric retroperitoneal and iliac lymph nodes. Levels of alpha-fetoprotein and human chorionic gonadotropin beta were normal. On positron emission tomography, the previously documented micronodular infiltrate exhibited features suggestive of an inflammatory etiology. The aspiration cytology of an iliac ganglion was described as normal, with no malignant cells. A liver biopsy revealed non-caseating epithelioid granulomas characteristic of granulomatous hepatitis. After exclusion of other causes of granulomatous inflammation, conjugation of clinical and histological features led us to the diagnosis of sarcoidosis with pulmonary, hepatic, splenic, and genitourinary involvement. This clinical report describes one of the rare occasions when the reproductive tract is affected by sarcoidosis and is the first organ to present signs of involvement by the disease, which reinforces the importance of considering sarcoidosis in the differential diagnosis of urologic conditions. The diagnosis of testicular sarcoidosis is challenging and the issue of its impact on fertility is particularly important.

Neurosyphilis: The Great Imitator.

Syphilis is a sexually transmitted disease caused by spirochete Treponema pallidum, with a growing incidence documented in recent years. Its clinical course is divided into three phases - primary, secondary, and tertiary syphilis - and virtually any organ can be affected, resulting in diverse clinical manifestations, making the diagnosis challenging. Neurosyphilis is a progressive, destructive disease of the central nervous system (CNS) that can develop at any stage of the infection, leading to meningeal involvement, meningovascular disease, or parenchymal syphilis (including tabes dorsalis and general paresis). Its clinical manifestations are heterogeneous and vary from focal neurologic signs to neuropsychiatric manifestations. The diagnosis is based mainly on the clinical picture and study of cerebrospinal fluid. Neuroimaging is helpful and sometimes essential, with magnetic resonance imaging being the most sensitive radiologic method, although there are no pathognomonic radiologic signs. Treatment of all forms of neurosyphilis is based on parenteral penicillin. We present a case of neurosyphilis in a patient presenting with a subacute confusional state and initial imaging findings suggestive of metastatic CNS lesions.

A Rare and Surprising Case of Spontaneous Type B Carotid-Cavernous Fistula in an Internal Medicine Ward.

Carotid-cavernous fistulas are abnormal communications between the carotid arteries and the cavernous sinus. They can be spontaneous, which is rare, or acquired, most often post-traumatic. We describe the case of a 59-year-old woman with complaints of right-sided red eye and blurred vision that did not improve with antibiotic treatment for bacterial conjunctivitis, progressing to what appeared to be post-septal cellulitis. The patient had exuberant chemosis, diplopia, VI cranial nerve palsy, and elevated intraocular pressure in the right eye. Computed tomography of the orbits showed right-sided thickening of the soft tissues of the upper eyelid and the medial and lateral rectus muscles, and an enlargement of the ipsilateral superior ophthalmic vein. However, antibiotics did not cause any kind of improvement. After a laborious diagnostic march, the diagnosis of a rare case of Barrow type B spontaneous carotid-cavernous fistula was confirmed. The patient underwent confirmatory angiography with endovascular treatment at the same time, showing rapid improvement after the procedure, without any sequelae. It is of great importance that clinicians are alert to this diagnosis, as diagnostic and therapeutic delay can lead to severe ocular compromise. In patients with a presumptive diagnosis of conjunctivitis and/or orbital cellulitis that does not improve with antibiotic treatment, the differential diagnosis with this rare entity should be considered, so that the appropriate treatment can be timely instituted.

Spinal Cord Infarction Presenting as Right-Sided Upper Back Pain: A Case Report.

Spinal cord infarction is a very rare event with a wide variety of symptoms at presentation. We describe the case of a 39-year-old man who presented to the emergency department with atypical chest pain. The initial investigations were non-diagnostic, and the patient was admitted for surveillance. On the second day of admission, he developed neurologic deficits; a second computed tomography showed a medullary infarction at levels C5-T2. Dual antiplatelet therapy was initiated. An extensive study on the underlying etiology was performed. It was considered to be an idiopathic event. The patient was discharged to a rehabilitation center for bladder training and motor training due to quadriplegia level D on Asia Impairment Scale with a C6 neurological level with left predominance and a hand grip deficit that disabled him to grab objects. This case report describes a rare event with a biphasic ictus at presentation. It highlights the difficulty in managing this pathology because of limited clinical data.

Isolated Left Ventricular Noncompaction Presenting With Heart Failure With Reduced Ejection Fraction and Intrahospital Cardiac Arrest: A Case Report and Literature Review.

Left ventricular noncompaction (LVNC) is characterized by a bilayered appearance of the myocardium with excessive trabeculations and deep intertrabecular recesses. Manifestations of this condition are widely variable, ranging from incidental findings in asymptomatic individuals to symptomatic heart failure, conduction abnormalities, tachyarrhythmia, and sudden cardiac death. Heart failure, ventricular arrhythmias, and systemic embolisms are the most frequent cardiovascular complications. We describe a case of a 53-year-old woman who presented to the emergency department with acute presentation of previously unknown heart failure with reduced ejection fraction and was diagnosed with LVNC. During hospitalization, the patient presented a defibrillated cardiac arrest rhythm, which was resuscitated after six minutes, and then treated with the placement of an implantable cardioverter defibrillator. After two years of follow-up with optimized medical therapy, the patient currently is asymptomatic and with a preserved ejection fraction.

Progressive Multifocal Leukoencephalopathy in a Chemotherapy-Naive Patient With Chronic Lymphocytic Leukemia: A Case Report.

Progressive multifocal leukoencephalopathy is a rare, progressive demyelinating disease of the central nervous system caused by reactivation and replication of the John Cunningham (JC) virus in cerebral oligodendrocytes. The JC virus is a small ubiquitous polyomavirus that can be detected in up to 50% of the adult population. It affects almost exclusively immunocompromised patients and is generally observed in patients with acquired immunodeficiency syndrome and patients with hematologic malignancies and autoimmune or chronic inflammatory diseases medicated with immunosuppressive and immunomodulatory drugs. However, it is rarely described in patients with hematologic malignancies, not undergoing chemotherapy or immunosuppressive therapy. It has a poor prognosis, and the treatment is based on restoring the immune system, given that no specific antiviral treatment is available. We present a case of a chemotherapy-naive patient with chronic lymphocytic leukemia associated with progressive multifocal leukoencephalopathy.