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Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.

BackgroundPredicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients.MethodsIntra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods.ResultsNetwork analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery.ConclusionsWe show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention.FundingNIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).

Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.

Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.

The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.

Correction to: Drug Delivery and Translational Research https://doi.org/10.1007/s13346-021-00920-x

Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.

Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients. Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods. Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery. We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention. NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).

Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.

Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.

Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Study designRetrospective analysis.ObjectiveTo assess the impact of mean arterial blood pressure (MAP) during surgical intervention for spinal cord injury (SCI) on motor recovery.SettingLevel-one Trauma Hospital and Acute Rehabilitation Hospital in San Jose, CA, USA.MethodsTwenty-five individuals with traumatic SCI who received surgical and acute rehabilitation care at a level-one trauma center were included in this study. The Surgical Information System captured intraoperative MAPs on a minute-by-minute basis and exposure was quantified at sequential thresholds from 50 to 104 mmHg. Change in International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor score was calculated based on physiatry evaluations at the earliest postoperative time and at discharge from acute rehabilitation. Linear regression models were used to estimate the rate of recovery across the entire MAP range.ResultsAn exploratory analysis revealed that increased time within an intraoperative MAP range (70-94 mmHg) was associated with ISNCSCI motor score improvement. A significant regression equation was found for the MAP range 70-94 mmHg (F[1, 23] = 5.07, r2 = 0.181, p = 0.034). ISNCSCI motor scores increased 0.039 for each minute of exposure to the MAP range 70-94 mmHg during the operative procedure; this represents a significant correlation between intraoperative time with MAP 70-94 and subsequent motor recovery. Blood pressure exposures above or below this range did not display a positive association with motor recovery.ConclusionsHypertension as well as hypotension during surgery may impact the trajectory of recovery in individuals with SCI, and there may be a direct relationship between intraoperative MAP and motor recovery.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Study designRetrospective analysis.ObjectiveTo assess the impact of mean arterial blood pressure (MAP) during surgical intervention for spinal cord injury (SCI) on motor recovery.SettingLevel-one Trauma Hospital and Acute Rehabilitation Hospital in San Jose, CA, USA.MethodsTwenty-five individuals with traumatic SCI who received surgical and acute rehabilitation care at a level-one trauma center were included in this study. The Surgical Information System captured intraoperative MAPs on a minute-by-minute basis and exposure was quantified at sequential thresholds from 50 to 104 mmHg. Change in International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor score was calculated based on physiatry evaluations at the earliest postoperative time and at discharge from acute rehabilitation. Linear regression models were used to estimate the rate of recovery across the entire MAP range.ResultsAn exploratory analysis revealed that increased time within an intraoperative MAP range (70-94 mmHg) was associated with ISNCSCI motor score improvement. A significant regression equation was found for the MAP range 70-94 mmHg (F[1, 23] = 5.07, r2 = 0.181, p = 0.034). ISNCSCI motor scores increased 0.039 for each minute of exposure to the MAP range 70-94 mmHg during the operative procedure; this represents a significant correlation between intraoperative time with MAP 70-94 and subsequent motor recovery. Blood pressure exposures above or below this range did not display a positive association with motor recovery.ConclusionsHypertension as well as hypotension during surgery may impact the trajectory of recovery in individuals with SCI, and there may be a direct relationship between intraoperative MAP and motor recovery.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

[Purpose]: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. Experimental Design: We have developed a new targeted nanomedicine based on hyaluronic acid–biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo., [Results]: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB., [Conclusions]: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.

Despite the convenience of the oral route for drug administration, the existence of different physiological barriers associated with the intestinal tract greatly lowers the bioavailability of many active compounds. We have previously suggested the potential polymeric nanocapsules, consisting of an oily core surrounded by a polymer shell, as oral drug delivery carriers. Here we present a systematic study of the influence of the surface properties of these nanocapsules on their interaction with the intestinal barriers. Two different surfactants, Pluronic®F68 (PF68) and F127 (PF127), and two polymeric shells, chitosan (CS) and polyarginine (PARG) were chosen for the formulation of the nanocapsules. We analyzed nine different combinations of these polymers and surfactants, and studied the effect of each specific combination on their colloidal stability, enzymatic degradation, and mucoadhesion/mucodiffusion. Our results indicate that both, the polymer shell and the surfactants located at the oil/water interface, influence the interaction of the nanocapsules with the intestinal barriers. More interestingly, according to our observations, the shell components of the nanosystems may have either synergic or disruptive effects on their capacity to overcome the intestinal barriers

A critical objective in cancer therapy is to reduce the systemic toxicity through the modification of the biodistribution of anticancer drugs. Herein, we disclose a new biodegradable nanocarrier, polyglutamic acid (PGA) nanocapsules, and present the in vivo pharmacokinetics/toxicity proof-of-concept for the anticancer drug plitidepsin. These novel nanocapsules were prepared using a modified solvent displacement technique where the polyamino acid was electrostatically deposited onto the lipid core. The nanocapsules exhibited an average size of 200 nm, a negative zeta potential and a great capacity for the encapsulation of plitidepsin (encapsulation efficiency above 90%). In addition, the nanocapsules could be freeze-dried and showed an adequate stability profile upon storage. Finally, the in vivo proof-of-concept studies performed in mice indicated that the encapsulation provided the drug with a prolonged blood circulation and a significantly reduced toxicity. In fact, the maximum tolerated dose of the nanoencapsulated drug was more than 3 times that of the reference formulation (Cremophor® EL plitidepsin solution). Overall, beyond the value of this specific formulation, the work reported here represents the evidence of the potential of polyamino acid nanocapsules in nano-oncological therapy

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Papers, Addresses, Reports: The Influence of Fungi in Human Affairs; The Fish Population of Sugar Creek, Illinois; Factors Influencing Excessive Flows of Coal Strip-Mine Effluents; Boat Fishermen's Catch at Crab Orchard Lake, Lake Murphysboro, and Horseshoe Lake, During 1955; Effect of Substrate Hydrogen Peroxide on Growth of Boron Deficient Plants; A Method for Obtaining Mitotic Figures in Seedlings of Alisma [Dill.] L.; The Gravel-Hill Prairies of Rock River Valley in Illinois; A Check-List of Illinois Myxomycetes; Polarography of Sulfhydryl-Disulfide Systems; Some Problems in the Synthesis of an Antimalarial Intermediate; Reaction of Ethylene Oxide with Antimony Chlorides; The Polarographic Determination of Sulfhydryl Groups; Differential Population Growth of Incorporated Municipalities in the Chicago Suburban Region; The Urbanization of Illinois; Patterns of Agricultural Change in Illinois; Rainfall on Jamaica; Urban and Non-urban Aspects of Manufacturing in Illinois; Plasticity Studies of Till Intruded into Jointed Limestone in Fairmount Quarry, Illinois; The Subsurface Glacial Geology at Proposed Effingham Damsite and Its Engineering Implications; A Pseudo-Ring Dike, Mt. Desert Island, Maine; Biocalcarenites in Some Upper Pennsylvanian Limestones in Illinois; Transmitting Motion Through the Walls of Sealed Vessels; Acoustic Problems of the Flute; A Philosophy of Science-Engineering Education; Writing the Scientific Paper; The Number of Species per Genus in Different Animal Classes in Illinois; Three New Species and Two New Records of Thrips (Thysanoptera) in Illinois; Cynticercua fasciolaris and Capillaria hepatica in Rattus norvegicus; Effect of Cardiac Glycosides on Potassium Content of Skeletal Muscle of Rana pipiens; A Comparison of Past and Present Populations of Freshwater Mussels in Southern Illinois; The Beaver in Illinois; Suburbanization of a Rural Trading Center; Non-Saponifiables from Deep-Fry Fats; Electrical Conductivities of Isomeric B

Dolores Navarro Torres (b. 1934) discusses her mother, Juanita Nieto Navarro, a recognized community organizer and activist in Houston beginning in the 1940s through the 1980s. Torres recalls her mother was a laundress and later a cook for the Shamrock Hotel, Rice Hotel, and Salvation Army senior citizen program. Nieto Navarro also cooked meals for activists and children who participated in Houston's strike schools, or huelga schools, in the 1970s. Nieto Navarro knew Cesar Chavez personally and recalls meeting Cantinflas. Nieto Navarro received the Fiestas Patrias Distinguished Mexican American of the Year Award in 1979. Torres talks about her childhood and life on the home front during World War II, and shares her thoughts on the legacy of the Northside community.