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Purpose:IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure.Experimental Design:We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis.Results:IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti–programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69−CD44+CD62L− T cells, reduction of CD86−PD-L1− M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use.Conclusions:IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system.See related commentary by Palanki et al., p. 5010

Supplementary Figure from Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors

Introducción: El aislamiento y el confinamiento son medidas de alto impacto social que, a nivel mundial y en mayor o menor grado de intensidad, han provocado cambio, temporales o permanentes, respecto a la forma en que se realizan las interacciones sociales. Objetivo: realizar un estudio en el ámbito de lo doméstico y de las modificaciones externas que obligaron a un encierro drástico en la población colombiana en los primeros meses de la pandemia por la COVID-19. Materiales y métodos: Se realizó un estudio con enfoque cualitativo a partir de la aplicación de entrevistas en profundidad a 45 participantes residentes en la ciudad de Bucaramanga, Colombia, logrando la reconstrucción de rutas de vida para evaluar el momento más drástico del encierro de la población. Resultados: Desde los hallazgos, se resalta la capacidad de asimilación de las fuertes medidas de confinamiento, la colectivización de las justificaciones más legitimadas desde el discurso médico y la construcción de medidas de autocuidado constituidas en el ámbito de lo doméstico como lugar y espacio relacional clave para enfrentar la incertidumbre social frente a la ausencia de respuestas efectivas para el control del contagio y de la enfermedad. Conclusión: El drástico encierro de la población colombiana a partir de las medidas transitorias, conlleva una alta incertidumbre de los grupos familiares, pero también una respuesta generalmente positiva.

Learning styles indicate the ways and conditions in which students understand, retain, and memorize knowledge in a productive and responsive manner. One of the most widely used tools to assess learning styles is the VARK (Visual, Aural, Read/write, and Kinesthetic) questionnaire. To identify the learning styles of students enrolled in three different dentistry programs in Brazil by applying the VARK questionnaire. This cross-sectional study involved a sample of 340 undergraduate students enrolled in dentistry programs at the following institutions: Federal University of Minas Gerais (n=172), Pontifical Catholic University of Minas Gerais (n=100), and Pontifical Catholic University of Paraná (n=68). An online questionnaire was administered to the students via “Qualtrics CM 2020”, between May 2020 and September 2020. It comprised questions about the student`s demographic, socioeconomic, and academic characteristics. Their learning style was assessed by the VARK questionnaire. The chi-squared test and Z-test were used to analyze the relationship between learning styles, considering p

Purpose: IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure. Experimental Design: We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis. Results: IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti–programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69−CD44+CD62L− T cells, reduction of CD86−PD-L1− M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use. Conclusions: IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system. See related commentary by Palanki et al., p. 5010

Background: Folate Receptor alpha (FRa) is a validated cell surface cancer target that is prevalently expressed in multiple cancers with high unmet need, including ovarian cancer and other gynecological cancers, while exhibiting minimal expression in normal tissues. Due to FRa’s favorable expression profile, multiple antibody-drug conjugates (ADCs) are being explored in this setting. Here we present the preclinical characterization of a new anti-FRa ADC, ZW191. ZW191 is an antibody drug conjugate (ADC) comprised of a humanized IgG1 antibody conjugated to a novel camptothecin-based topoisomerase 1 inhibitor payload, ZD06519, via a maleimidocaproyl (MC) anchor and a glycyl glycyl phenylalanyl glycine (GGFG)-aminomethyl (AM) cleavable linker at a drug-to-antibody ratio (DAR) of 8. Materials and Methods: The novel antibody and drug-linker components of ZW191 were generated, characterized, and optimally integrated. The apparent binding affinity and cellular internalization of the ZW191 antibody, and the intracellular concentration of the released camptothecin payload, ZD06519, were determined in FRa-expressing cells. Additionally, the binding specificity of the ZW191 antibody was determined using a cell microarray technology to test for binding against over 6,000 full length proteins that are individually over-expressed in human cells. Tumor spheroid cancer cell cultures were utilized to determine the cytotoxicity of ZW191 and the ability of ZW191 to penetrate the layers of the three-dimensional (3D) spheroid. The bystander activity of ZW191 was assessed using antigen positive and negative co-culture experiments. The anti-tumor activity of ZW191 was evaluated in a panel of cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) ovarian cancer models spanning a range of FRa expression. ZW191 was evaluated in toxicology and pharmacokinetic (PK) studies performed in rodents and non-human primates (NHP). Results: The antibody component of ZW191 features a favorable binding profile with strong and exclusive binding to FRa, and drives superior tumor spheroid penetration, cellular internalization, and payload delivery compared to FRa targeted antibodies used in other ADCs. ZW191 demonstrates potent activity in FRa expressing 3D tumor spheroid cultures and effective bystander activity. In a panel of CDX and PDX models representing a range of FRa expression, ZW191 demonstrates compelling anti-tumor activity at exposures that are estimated to be readily achievable in the clinic. ZW191 was tolerated up to 200 mg/kg in a two-dose rat study and at 30 mg/kg in a two-dose NHP study, with favorable PK. The promising efficacy, tolerability, and PK supports the potential of ZW191 as a novel therapeutic agent that may help address unmet need in patients with high and low FRa-expressing cancers. Citation Format: Sam Lawn, Andrea Hernandez Rojas, Raffaele Colombo, Dayananda Siddappa, Jodi Wong, Kaylee Wu, Vincent Fung, Dunja Urosev, Luying Yang, Jamie R. Rich, Stuart D. Barnscher. ZW191, a novel FRa-targeting antibody drug conjugate bearing a topoisomerase 1 inhibitor payload [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2641.

Biomaterials induced host immune responses, and fibrotic overgrowth remains a major barrier to the long-term function of medical devices and biomaterial consisting of tissue grafts. Screening new biomaterials to identify anti-fibrotic formulation requires in vivo testing, which is challenging to multiplex and remains a significant obstacle to progress in this field. Herein, we synthesized a combinatorial chemically modified hydrogel library and developed a cellular barcoding method that enables high-throughput multiplexed in vivo screening of 20 formulations in a single mouse and 100 formulations in a single non-human primate. Our screening method consists of implanting a mixture of biomaterials and each barcoded with human umbilical vein epithelial cells (HUVEC) from different individual donors. Single nucleotide polymorphism (SNP) genotypes of the cells were utilized as readouts using next-generation sequencing (NGS) to pair the material identity with material performance. Screening of the library using a xenogeneic transplantation model identified three novel lead hydrogel formulations (Z4-A10, Z1-A3, and Z2-A19) with improved anti-fibrotic properties that enable long-term cell viability. Z4-A10 was used to encapsulate human islets and validated for long-term glycemic control in an STZ-induced C57BL/6J diabetic mouse model. Leads, Z1-A3 and B2-A17, were further validated as immunomodulating coatings for medical-grade catheters to prevent fibrosis and occlusion, highlighting the translation of our screening approach and findings to other medical devices. Our results suggest that the developed cellular barcoding method and in vivo multiplexed screening technique can be leveraged to identify biomaterials for a wide range of clinical applications. Significantly, our newly discovered leads can improve the long-term performance of medical devices and encapsulated cell-based therapeutics.

Objectives The 2014 Bethesda System (TBS 2014) guidelines for reporting cervical cytology revised the age for reporting benign endometrial cells (BECs) from 40 years or older to age 45 years or older. We evaluated this change and further investigated if extending the reporting age to 50 years or older may be acceptable. Methods We reviewed cases with BECs reported on Papanicolaou tests in women age 40 years or older and 45 years or older before and after implementation of TBS 2014. Follow-up endometrial biopsy/curettage results were categorized as benign, endometrial hyperplasia with or without atypia, or malignant. Hyperplasia and malignant follow-up were considered clinically significant. Clinical data were documented. Results were compared for women age 40 to 44, 45 to 49, and 50 years or older. Results Follow-up in 15 (100%) women age 40 to 44 years was benign. In women age 45 to 49 years, 61 (96.8%) had benign follow-up, one (1.6%) had atypical hyperplasia, and one (1.6%) had malignant follow-up. In women age 50 years or older, 57 (86.5%) had benign follow-up, four (6%) had malignant follow-up, and seven (7.5%) had atypical or nonatypical hyperplasia. There was a significant difference in follow-up between the age groups of 40 to 49 and 50 or older (P = .023). Conclusions We conclude that the TBS 2014 revision was justified. Our data suggest that age 50 years or older rather than age 45 years or older may be an acceptable cutoff for reporting BECs.

Code and data used in the theoretical model of intraperitoneal cytokine delivery used in the publication., Funding Sources: Cancer Prevention Research Institute of Texas grant RR160047 (OV) Avenge Bio Sponsored Research Agreement to Rice University (OV) and Cell Trans (JO) Emerson Collective (AJ, WP) Welch Foundation (OI, ADH) Rice University Academy Fellowship (MJ) National Science Foundation grant 1842494 (AN) National Institute of Health grant 1RO1DK120459-01 (AN, OV)

Acute glomerulonephritis is a constellation of renal disorders which are precipitated by an immunologic mechanism triggering inflammation and proliferation of glomerular tissue resulting in damage to the basement membrane, mesangium, or capillary endothelium. Two of the most well-known manifestations of glomerulonephritis are granulomatosis with polyangiitis (GPA) and IgA nephropathy (IgAN). To our knowledge, these diseases are often found separately and are rarely diagnosed in the same patient. Here, we discuss a case of a 35-year-old male who presented and was diagnosed with simultaneous GPA and IgAN. His renal biopsy was significant for extensive, crescentic, and necrotizing glomerulonephritis and IgA staining on immunofluorescence indicating severe renal damage. Despite full immunosuppressive therapy, our patient failed to recover his renal function. In our case, we hope to raise awareness of these disorders and early recognition of the clinical features. We believe that this case would prompt providers to pursue diagnostic workups to detect these diseases early on, especially when symptoms progressively worsen and become systemic. As demonstrated in our patient, delay in diagnosis can lead to irreversible damage to a patient’s renal function, especially when two types of glomerulonephritis are present.

Os estilos de aprendizagem indicam as formas e condições em que os alunos compreendem, retêm e memorizam o conhecimento de forma produtiva e responsiva. Uma das ferramentas mais utilizadas para avaliar estilos de aprendizagem é o questionário VARK (Visual, Auditivo, Escrita/Leitura e Cinestésico). Foram avaliados os estilos de aprendizagem de alunos matriculados em três diferentes cursos de odontologia no Brasil por meio da aplicação do questionário VARK. Este estudo transversal envolveu uma amostra de 340 alunos de graduação matriculados em cursos de odontologia das seguintes instituições: Universidade Federal de Minas Gerais (n=172), Pontifícia Universidade Católica de Minas Gerais (n=100) e Pontifícia Universidade Católica do Paraná (n=68). Um questionário online foi aplicado aos alunos via “Qualtrics XM 2020”, entre maio de 2020 e setembro de 2020. Era composto por perguntas sobre características demográficas, socioeconômicas e acadêmicas do aluno. Seu estilo de aprendizagem foi avaliado pelo questionário VARK. O teste qui-quadrado e o teste Z foram utilizados para analisar a relação entre os estilos de aprendizagem, considerando p

Immunomodulatory therapeutics represent a unique class of drug products that have tremendous potential to rebalance malfunctioning immune systems and are quickly becoming one of the fastest-growing areas in the pharmaceutical industry. For these drugs to become mainstream medicines, they must provide greater therapeutic benefit than the currently used treatments without causing severe toxicities. Immunomodulators, cell-based therapies, antibodies, and viral therapies have all achieved varying amounts of success in the treatment of cancers and/or autoimmune diseases. However, many challenges related to precision dosing, off-target effects, and manufacturing hurdles will need to be addressed before we see widespread adoption of these therapies in the clinic. This review provides a perspective on the progress of immunostimulatory and immunosuppressive therapies to date and discusses the opportunities and challenges for clinical translation of the next generation of immunomodulatory therapeutics.

Context.— Gender-affirming surgery is part of a multidisciplinary approach in gender transitioning. Deeper histologic examination may strengthen care for transmasculine individuals and increase the understanding of the influence of hormonal therapy in specific organs. Objective.— To evaluate and catalogue histologic findings of tissue obtained from gender-affirming gynecologic surgery and cervical cytology specimens. Design.— This is an institutional review board–approved retrospective study that included transmasculine individuals who underwent gender-affirming gynecologic surgery from January 2015 to June 2020. All surgical gynecologic pathology and cervical cytology slides were reviewed by 2 pathologists. Results.— Fifty-five patients were included, which represented 40 uteri, 35 bilateral ovaries, 15 vaginectomy specimens, and 24 cervical cytology results. The median age was 27 years (range, 18–56), and 94% (50 of 53) of patients were receiving testosterone for at least 1 year. Seventy-five percent (30 of 40) of endometria were inactive, while 25% (10 of 40) showed evidence of cycling. Transitional cell metaplasia was the most common finding in the cervix (17 of 40) and vagina (15 of 15), reflecting a high percentage (4 of 24) of unsatisfactory or ASC-US (atypical squamous cells of undetermined significance) cervical cytologies. Prostatic-type glands were identified in 20% (8 of 40) of cervices and 67% (10 of 15) of vaginectomy specimens. Multiple bilateral cystic follicles and evidence of follicular maturation were present in 57% (20 of 35) of cases. Four cases showed paratubal epididymis-like mesonephric remnant hypertrophy. Conclusions.— A comprehensive evaluation of tissue from gender-affirming surgery increases knowledge of the changes following androgen therapy in transmasculine individuals and may contribute to optimal patient care by raising awareness of normal histologic variations in this population.

International audience; Lanthipeptides, ribosomally synthesized and post-translationally modified peptides (RiPPs), can be divided into five classes based on their structures and biosynthetic pathways. Class I and II lanthipeptides have been well characterized, whereas less is known about members of the other three classes. Here, we describe a new family of class III lanthipeptides from Firmicutes. Members of the family are distinguished by the presence of a single carboxy-terminal labionin. We identified and characterized andalusicin, a representative of this family. Andalusicin bears two methyl groups at the alpha-amino terminus, a post-translational modification that has not previously been identified in class III lanthipeptides. Mature andalusicin A shows bioactivity against various Gram-positive bacteria, an activity that is highly dependent on the alpha-N dimethylation.

A 11‐year‐old male neutered Shih Tzu was referred to a tertiary facility with a history of weight loss, decreased appetite, polydipsia, and lethargy. The dog had a 10‐year history of nonspecific allergic dermatitis and was being treated with 16 mg/kg of ketoconazole q12h for Malassezia dermatitis. Vague gastrointestinal signs, hypocholesterolemia, and lack of a stress leukogram increased suspicion for hypoadrenocorticism (HA). An adrenocorticotropic hormone (ACTH) stimulation test identified hypocortisolemia on pre‐ and post‐ACTH samples and ketoconazole was discontinued. After a short course of corticosteroid treatment, an ACTH stimulation test was repeated and pre‐ACTH cortisol concentration was within the reference range, and the post‐ACTH cortisol concentration was mildly increased. The temporal association between return of adequate adrenocortical cortisol production and discontinuation of ketoconazole led to the conclusion that the dog had developed iatrogenic HA secondary to ketoconazole treatment.

Pancreatic cancer is often diagnosed at advanced stages and responds poorly to chemotherapy. Because high tumor T cell infiltration corresponds with better clinical outcomes in pancreatic cancer patients, immunotherapy has gained significant interest over the last decade for the treatment of recurrent pancreatic cancer. IL-12 is a proinflammatory cytokine with pleiotropic effects including activation of CD8+ T cells and NK cells. Unfortunately, systemic high dose IL-12 administration led to severe toxicities in clinical trials which has limited further development of this cytokine as a cancer therapeutic. To address this limitation, we developed an implantable cytokine delivery platform to allow for local administration of IL-12. These cytokine factories, composed of genetically engineered epithelial cells encapsulated in biocompatible polymers, allow for safe and controlled dosing in vivo. Tumor adjacent administration of IL-12-based cytokine factories caused reduction of intraperitoneal pan02 tumor burden by 80% after only 1 week of treatment in mice with pancreatic cancer. Single cell RNAseq of the tumor adjacent immune cells at this time point showed 2x more T and NK cells present in the IL-12 treated mice than untreated mice suggesting modulation of the tumor microenvironment via immune cell infiltration. Importantly, the necessary IL-12 dose was well tolerated in all mice without signs of toxicity for 180 days. In efforts to evaluate the translatability of this platform, we further tested IL-12-based cytokine factories in a non-human primate. The cytokine factories produced a high local IL-12 concentration without substantial leakage into the systemic circulation and were well tolerated by the primates as shown by the lack of fever or weight loss, as well as the lack of renal or liver toxicity. Our findings highlight the therapeutic potential of IL-12 treatments when administered locally via cytokine factories in preclinical animal models. Further, these findings provide rationale for future development and clinical testing of cytokine factories for treatment of a wide range of metastatic peritoneal cancers in humans. Citation Format: Amanda Nash, Samira Aghlara-Fotovat, Bertha Castillo, Annie Nguyen, Andrew Cui, Andrea Hernandez, Peter Rios, Sofia Ghani, Ira Joshi, Chunyu Xu, Rahul Sheth, Weiyi Peng, Jose Oberholzer, Amir Jazaeri, Omid Veiseh. IL-12-based cytokine factories modulate tumor microenvironment to eradicate pancreatic tumors in mice and are well tolerated in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3547.

Pro-inflammatory cytokines have been approved as a cancer immunotherapy for treatment of metastatic melanoma and renal carcinoma for over 30 years. However, widespread use of cytokine therapy in the clinic is limited by its short half-life in circulation and the associated toxicities that emerge as a result of high systemic exposure. To overcome these limitations, we developed a clinically translatable cytokine delivery platform, called cytokine factories, composed of genetically engineered epithelial cells encapsulated in biocompatible polymers. These cells are able to produce a wide range of natural cytokines (IL2, IL7, IL10, or IL12) and allow for controlled and predictable dosing in vivo. In vivo administration of cytokine factories created a high local cytokine concentration (IP space) without substantial leakage into the systemic circulation. Local, or tumor adjacent, administration of pro-inflammatory (IL-2-based) cytokine factories caused reduction of tumor burden by 70% after only 1 week of treatment when delivered as a monotherapy to mice with malignant pleural mesothelioma (MPM). Importantly, when administered in combination with local anti-PD1 injections, these cytokine factories lead to eradication of these highly aggressive tumors in 7/7 treated mice. To validate the translatability of this platform, we evaluated the safety profile in non-human primates. Significantly, this platform produced local and systemic T cell biomarker profiles that predict efficacy without renal, liver, or general toxicity in non-human primates. Our findings demonstrate the safety and efficacy of cytokine factories in preclinical animal models and provide rationale for future clinical testing for the treatment of metastatic peritoneal cancers in humans. Citation Format: Amanda Nash, Samira Aghlara-Fotovat, Andrea Hernandez, Bertha Castillo, Alexander Lu, Aarthi Pugazenthi, Peter Rios, Sofia Ghani, Ira Joshi, Douglas Isa, Chunyu Xu, Rahul Sheth, Weiyi Peng, Jose Oberholzer, Amir Jazaeri, Hee-Jin Jang, Bryan Burt, Hyun-Sung Lee, Ravi Ghanta, Omid Veiseh. Evaluation of implantable cytokine factories in combination with checkpoint inhibitors for eradication of malignant pleural mesothelioma (MPM) tumors in mice with safe and predictable dosing in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4189.

The synthesis and characterization of a family of [60]fullerocurcuminoids obtained via Bingel reactions is reported., The synthesis and characterization of a family of [60]fullerocurcuminoids obtained via Bingel reactions is reported. The new C60 derivatives include curcumin and curcuminoids with a variety of end groups. Preliminary biological experiments show the potential activity of the compound containing a curcumin addend, which exhibits moderate anti-HIV-1 and radical scavenger properties, but no anti-cancer activity. In addition, the new fullerocurcuminoids exhibit HOMO/LUMO energy levels that are reasonably matched with those of perovskites and when they were tested in perovskite solar cells (PSCs) as the electron transporting material (ETM), photoconversion efficiencies ranging from 14.04–14.95% were obtained, whereas a value of 16.23% was obtained for [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) based devices.

Korsakoff syndrome is a neuropsychiatric condition frequently seen as a progression of Wernicke’s encephalopathy and is often associated with long-term alcohol abuse. It is characterized by further cognitive impairments, such as indiscriminate anterograde and retrograde amnesia, in addition to executive function deficits. As the syndrome is a result of severe thiamine deficiency, its management primarily focuses on nutritional replenishment and electrolyte maintenance. In recent years, a few published reports have detailed the off-label use of Food and Drug Administration (FDA) approved drugs for Alzheimer’s in an attempt to treat neurocognitive deficits associated with Korsakoff patients. In this particular case, we note subjective improvement in cognition after initiating memantine, an N-Methyl-d-aspartate (NMDA) receptor antagonist.

Pembrolizumab is an immunoglobulin G4 (IgG4) monoclonal antibody used in the treatment of various types of cancers. Despite its efficacy, pembrolizumab does not specifically target cancer cells which often leads to common side effects seen in immunotherapies such as diarrhea, rash, fatigue, nausea, decreased appetite, pruritus, and endocrinopathies. Type 1 diabetes mellitus (T1DM) has been reported in 0.1% of the patients in pembrolizumab clinical trials. In this case report, we discuss a 65-year-old Caucasian male with a history of metastatic head and neck cancer that was previously treated with pembrolizumab and was subsequently admitted to the intensive care unit (ICU) due to new onset diabetic ketoacidosis (DKA). Based on the timing of his presentation and the pre-hospital/inpatient workup, notably a normal hemoglobin A1C (HbA1c) 72 hours prior to admission and a significant increase thereafter, it was concluded that his presentation of diabetic ketoacidosis was secondary to his most recent infusion of pembrolizumab. With immunotherapies like programmed cell death (PD1) receptor antibodies becoming a more common first-line treatment for various cancers, this case hopes to raise awareness about the possible endocrinologic-related adverse events to its use and may help guide outpatient management.

Carboxylic acids obtained via the microbial electrochemical conversion of waste gases containing carbon dioxide (i.e., microbial electrosynthesis) can be used in lieu of nonrenewable building-block chemicals in the manufacture of a variety of products. When targeting valuable medium-chain carboxylic acids such as caproic acid, electricity-driven fermentations can be limited by the accumulation of fermentation products in the culturing media, often resulting in low volumetric productivities and titers due to direct toxicity or inhibition of the biocatalyst. In this study, we tested the effectiveness of a simple electrodialysis system in upconcentrating carboxylic acids from a model solution mimicking the effluent of a microbial electrochemical system producing short- and medium-chain carboxylic acids. Under batch extraction conditions, the electrodialysis scheme enabled the recovery of 60% (mol mol-1) of the total carboxylic acids present in the model fermentation broth. The particular arrangement of conventional monopolar ion exchange membranes and hydraulic recirculation loops allowed the progressive acidification of the extraction solution, enabling phase separation of caproic acid as an immiscible oil with 76% purity. publishedVersion

Dermatophytosis is a common and highly contagious zoonotic skin disease in companion animals. This disease is a major concern in geographical areas that contain large numbers of stray animal populations. Numerous surveys on dermatophytosis among stray animal populations worldwide range between 27% to 50%. In recent years, the US territory of Puerto Rico was impacted by several natural disasters such as hurricanes, which has led to a large increase of abandonment cases and an increase in the stray animal population. Due to this, large low-cost spay/neuter clinics and trap-neuter-release programs have become a more common practice on the island. During these events, veterinary staff are exposed to multiple animals with no health history, and therefore, zoonotic diseases are of concern. The aim of this study was to provide information regarding the presence of dermatophyte species in symptomatic and asymptomatic stray dogs and cats in a region of Puerto Rico. Hair samples were collected from 99 stray animals with and without dermatological clinical signs. The hair samples were cultured on plates containing rapid sporulation medium and dermatophyte test medium. All cultures were evaluated microscopically to confirm the presence of dermatophytes. Then, all dermatophytes were further evaluated with MALDI-TOF MS to compare both diagnostic tests. A total of 19 animals (19%) were positive for dermatophyte growth. Of these animals, 18/19 were infected with M. canis and 1/19 with Trichophyton spp. Animals with clinical lesions were positive only 13.5% of the time compared to asymptomatic animals, who were positive in 36% of the sample population. All 19 dermatophytes (100%) diagnosed with microscopic evaluation were confirmed with MALDI-TOF MS. Our results indicate that there is a prevalence of 19% of dermatophytosis among the stray dog and cat population of the southeastern coast of the island.

Pasteurella multocida (P. multocida) is a zoonotic organism found in the normal flora of domestic and wild animals. In this case report, we present a 70-year-old Caucasian male who presented with fever, chills, and greenish sputum which began hours prior to presentation. His symptoms were initially thought to be due to refractory pneumonia because the patient had been discharged from our hospital three weeks prior to presentation. Blood cultures grew P. multocida, a rare pathogen to cause bacteremia. He was treated with cefepime and later amoxicillin/clavulanic acid and made an uneventful recovery. Later history of the patient's cats scratching him was thought to be the mode of transmission. P. multocida infection is rare, and can also be dangerous and even fatal in immunocompromised individuals. Clinicians must therefore operate with a high degree of suspicion especially when treating immunocompromised patients with bacteremia.

Summary Lanthipeptides, ribosomally synthesized and post-translationally modified peptides (RiPPs), can be divided into five classes based on their structures and biosynthetic pathways. Class I and II lanthipeptides have been well characterized, whereas less is known about members of the other three classes. Here, we describe a new family of class III lanthipeptides from Firmicutes. Members of the family are distinguished by the presence of a single carboxy-terminal labionin. We identified and characterized andalusicin, a representative of this family. Andalusicin bears two methyl groups at the α-amino terminus, a post-translational modification that has not previously been identified in class III lanthipeptides. Mature andalusicin A shows bioactivity against various Gram-positive bacteria, an activity that is highly dependent on the α-N dimethylation., Graphical abstract, Highlights • Type III lanthipeptide andalusicin A inhibits the growth of Gram-positive bacteria • Andalusicin A has an unusual pastor's crook structure • Genes encoding methyltransferases are frequently found in andalusicin-like BGCs • N-terminal methylation is necessary for andalusicin A biological activity, Chemistry; Biosynthesis; Biochemistry; Medical biochemistry

Aim To examine the role of Adult Protective Services' (APS's) nurses in helping abused, neglected and exploited older people, this study investigated how nurses' contribution differs from social workers. Though the majority of APS' workforce is staffed by social workers, some programmes also employ nurses. Design Secondary data analysis using convergent parallel mixed-method design was conducted. Methods Using survey data from the National Adult Protective Services Association, 99 nurses' responses between October 2014 and August 2015 were analysed to examine their agency characteristics, training and qualities, job responsibilities and interprofessional collaboration. Results The majority of nurses work with social workers or other professionals using a multidisciplinary team (MDT) approach. Among those carrying a caseload, 69% (49 out of 71) of nurses work in conjunction with social workers. Out of all nurses, 64% (63 out of 99) indicated participation in at least one MDT. While the responsibilities nurses provided were similar to social workers, nurses were also able to provide healthcare related services, in their professional competencies, without referral. Conclusion Nurses in APS are in a privileged position to investigate mistreatment and provide/coordinate direct care for victims. Impact Not much was known about nurses who directly investigate elder mistreatment and provide services to victims. This study was the first to highlight the nursing workforce in APS, and described the nurses' unique contribution to the field. Nurses functioned as both social workers and healthcare professionals in APS. Since victims of elder mistreatment often suffer from negative physical, psychological and social consequences, having nurses in APS benefits victims to receive and the programmes in providing better care and services.

Acute pancreatitis is an acute inflammatory process of the pancreas that is associated with multiple etiologies. The two most common causes are gallstones and acute alcohol intoxication. However, medications are often overlooked when determining the cause. Empagliflozin is a type of sodium-glucose transport protein 2 (SGLT-2) inhibitor used for the treatment of type 2 diabetes mellitus. Given that this medication is new, the adverse effects have not been fully reported in the literature. Currently, the most commonly reported side effects are genitourinary infections such as cystitis or yeast infection although acute pancreatitis as a result of empagliflozin is very rare. Here, we discuss a case of a 64-year-old female who presented with severe pancreatitis after recently initiating the use of empagliflozin. Based on the timing of her presentation and her hospital workup to rule out many of the common etiologies, it was concluded that empagliflozin was the likely cause of her acute pancreatitis. With SGLT-2 inhibitors such as empagliflozin, becoming popular as first-line in the management of diabetes, this case may hope to raise awareness of the possible adverse effects related to it. Additionally, this case also emphasizes the importance of identifying iatrogenic related pancreatitis.