Search

Mutations in ENT3, encoded by SLC29A3, result in anaemia and erythroid hypoplasia, suggesting roles in erythropoiesis. Here the authors show that ENT3 acts as a lysosomal bile acid transporter, and mutation compromises taurine conjugated bile acid transport in erythroid progenitors leading to ER stress, and anaemia.

Protein kinases have emerged as critical regulators of disease pathogenesis. Here, the authors have utilized kinome-wide screening approaches to reveal a pathogenic role of CDKL5 kinase in acute kidney injury, which is dependent on suppression of a SOX9-associated transcriptional network.

Summary: The involvement of membrane-bound solute carriers (SLCs) in neoplastic transdifferentiation processes is poorly defined. Here, we examined changes in the SLC landscape during epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. We show that two SLCs from the organic anion/cation transporter family, SLC22A10 and SLC22A15, favor EMT via interferon (IFN) α and γ signaling activation of receptor tyrosine kinase-like orphan receptor 1 (ROR1) expression. In addition, SLC22A10 and SLC22A15 allow tumor cell accumulation of glutathione to support EMT via the IFNα/γ-ROR1 axis. Moreover, a pan-SLC22A inhibitor lesinurad reduces EMT-induced metastasis and gemcitabine chemoresistance to prolong survival in mouse models of pancreatic cancer, thus identifying new vulnerabilities for human PDAC.

Mutations in equilibrative nucleoside transporter 3 (ENT3), encoded by SLC29A3, cause a spectrum of human genetic disorders. Here, the authors show altered haematopoietic stem cell and mesenchymal stem cell fates in ENT3-deficient mice, due to misregulation of the AMPK-mTOR-ULK axis.

Thymic tumors have an overall annual incidence rate of around 0.15 to 0.6 cases per 100,000 individuals. Primary neuroendocrine tumors of thymus are estimated to account for 2% to 5% of all thymic neoplasms and are extremely rare with an incidence of 0.18 among 1,000,000 persons every year1. Thymic neuroendocrine tumors are known to be more aggressive than other foregut neuroendocrine tumours.2 A third of these tumors are asymptomatic and discovered incidentally; 50% are functionally active and present with paraneoplastic syndromes, and around 20% have metastasis at presentation. We present a case of PNETT with typical features who presented with mediastinal compressive symptoms with metastasis who we managed using recent guidelines. [ABSTRACT FROM AUTHOR]

Abstract Background The characteristics of a tumor are largely determined by its interaction with the surrounding micro-environment (TME). TME consists of both cellular and non-cellular components. Cancer-associated fibroblasts (CAFs) are a major component of the TME. They are a source of many secreted factors that influence the survival and progression of tumors as well as their response to drugs. Identification of markers either overexpressed in CAFs or unique to CAFs would pave the way for novel therapeutic strategies that in combination with conventional chemotherapy are likely to have better patient outcome. Methods Fibroblasts have been derived from Benign Prostatic Hyperplasia (BPH) and prostate cancer. RNA from these has been used to perform a transcriptome analysis in order to get a comparative profile of normal and cancer-associated fibroblasts. Results The study has identified 818 differentially expressed mRNAs and 17 lincRNAs between normal and cancer-associated fibroblasts. Also, 15 potential lincRNA-miRNA-mRNA combinations have been identified which may be potential biomarkers. Conclusions This study identified differentially expressed markers between normal and cancer-associated fibroblasts that would help in targeted therapy against CAFs/derived factors, in combination with conventional therapy. However, this would in future need more experimental validation.

Abstract In this research work, optimized nebivolol-loaded lecithin-chitosan hybrid nanoparticles (NEB-LCNPs) were prepared using sequential screening and optimization designs. The design of experiments software (DoE) was used to obtain a robust formulation that can improve ocular delivery of the NEB in the treatment of glaucoma. The optimized NEB-LCNPs had a mean particle size of 170.5 ± 5.3 nm and drug loading of 10.5 ± 1.2%. These were further loaded in a dual-responsive in situ gel, designed and reported previously by our group. The NEB-LCNPs loaded in situ gel (NEB-LCNPs-ISG) was characterized for physicochemical properties, rheological behavior, stability, in vitro dissolution, and ocular in vivo studies. The ocular pharmacokinetics showed that NEB-LCNPs-ISG had two-fold higher aqueous humor exposure with AUC0–tlast of 375.4 ng × h/mL and sustained drug concentrations for longer durations (1.7-folds higher duration with a mean residence time of 10.6 h) in comparison to a conventional aqueous suspension of NEB (NEB-Susp). Similarly, the pharmacodynamic study showed that NEB-LCNPs-ISG resulted in a higher percentage reduction in intraocular pressure (% ΔIOP) of 28.1 ± 1.8% × h, which was 2.2-times higher reduction compared to NEB-Susp (74.2 ± 3.2% × h). In addition, the pharmacodynamic effect was more sustained with a mean response time of 11.3 ± 0.2 h, a 2.8-times higher response time compared to NEB-Susp (4.06 ± 0.3 h). These results suggest that NEB-LCNPs-ISG was more effective than the conventional aqueous suspension of NEB in the treatment of glaucoma.

Nebivolol hydrochloride (NEB), a 3rd-generation beta-blocker, was recently explored in managing open-angle glaucoma due to its mechanism of action involving nitric oxide release for the vasodilation. To overcome the issue of low ocular bioavailability and the systemic side effects associated with conventional ocular formulation (aqueous suspension), we designed and optimized polycaprolactone polymeric nanoparticles (NEB-PNPs) by applying design of experiments (DoE). The particle size and drug loading of the optimized NEB-PNPs were 270.9 ± 6.3 nm and 28.8 ± 2.4%, respectively. The optimized NEB-PNPs were suspended in a dual-sensitive in situ gel prepared using a mixture of P407 + P188 (as a thermo-sensitive polymer) and κCRG (as an ion-sensitive polymer), reported previously by our group. The NEB-PNPs-loaded in situ gel (NEB-PNPs-ISG) formulation was characterized for its rheological behavior, physical and chemical stability, in vitro drug release, and in vivo efficacy. The NEB-PNPs-loaded in situ gel, in ocular pharmacokinetic studies, achieved higher aqueous humor exposure (AUC0–t = 329.2 ng × h/mL) and for longer duration (mean residence time = 9.7 h) than compared to the aqueous suspension of plain NEB (AUC0–t = 189 ng × h/mL and mean residence time = 6.1 h) reported from our previous work. The pharmacokinetic performance of NEB-PNPs-loaded in situ gel translated into a pharmacodynamic response with 5-fold increase in the overall percent reduction in intraocular pressure by the formulation compared to the aqueous suspension of plain NEB reported from our previous work. Further, the mean response time of NEB-PNPs-loaded in situ gel (12.4 ± 0.6 h) was three times higher than aqueous suspension of plain NEB (4.06 ± 0.3 h).

Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. NM is orally administered at a high dose of 290 mg due to its low solubility and poor dissolution rate at pH > 3, as well as gut-wall metabolism limiting its bioavailability. Self-emulsifying drug delivery systems (SEDDSs) of NM were developed in the current study to improve its oral bioavailability. The oily vehicle (clove oil) was selected based on the solubility of NM, while the surfactant and the cosurfactant were selected based on the turbidimetric analysis. Three different sets were screened for surfactant selection in the preparation of SEDDS formulations, the first set containing Cremophor® EL alone as the surfactant, the second set containing a mixture of Cremophor® EL (surfactant) and Caproyl® PGMC (cosurfactant), and the third set containing a mixture of Cremophor® EL (surfactant) and Capmul® MCM C8 (cosurfactant). Propylene glycol was used as the cosolubilizer in the preparation of SEDDSs. A series of studies, including the construction of ternary phase diagrams to determine the zone of emulsification, thermodynamic stability studies (involving dilution studies, freeze-thaw, and heating–cooling studies), turbidimetric analysis, and physicochemical characterization studies were conducted to identify the two most stable combinations of SEDDSs. The two optimized SEDDS formulations, TP16 and TP25, consisted of clove oil (45% w/w) and propylene glycol (5% w/w) in common but differed with respect to the surfactant or surfactant mixture in the formulations. TP16 was prepared using a mixture of Cremophor® EL (surfactant) and Caproyl® PGMC (cosurfactant) in a 4:1 ratio (50% w/w), while TP25 contained only Cremophor® EL (50% w/w). The mean globule sizes were 239.8 ± 77.8 nm and 204.8 ± 2.4 nm for TP16 and TP25, respectively, with an emulsification time of p < 0.05) and 2.24 (p < 0.01), respectively.

• We report a case of a 52-year-old male patient who presented with features of mass per rectum, which on first look appeared to be a full thickness prolapse of the rectum. • On careful examination, it turned out to be intussusception of colonic growth through anal canal. • Contrast Enhanced Computed Tomography showed features of colonic obstruction. • Sigmoidal growth intussuscepting through anal canal is extremely rare with only 9 cases being reported in Literature till date. • He underwent sigmoidectomy with Hartman's procedure uneventfully. • A high index of suspicion is imperative to diagnose & treat such a case in timely manner to avoid lethal outcomes. Introduction – In adults, protrusion of intussuscepted sigmoid growth through the anal canal is exceedingly rare, with only 9 cases being reported till date. Case Report – A 52-year old man presented to emergency department with what appeared to be an episode of rectal prolapse following straining while defaecating. On examination, he had a prolapsed 8 × 8 cm bowel, with a 2 × 2 cm friable villous growth as the lead point, with space between the mass and the perianal skin. Computed Tomography of the abdomen was done which was suggestive of telescoping of the sigmoid into the rectum protruding out through the anal canal with features of intestinal obstruction. He underwent exploratory laparotomy with sigmoidectomy with Hartman's Procedure. Post-operative period was uneventful. Histopathology was suggestive of moderately differentiated carcinoma. Discussion – In colo-anal intussusception, as was in our patient, the preferred approach is to reduce the intussusception before resection, to perform a sphincter saving operation as compared to an Abdominoperineal Resection (APR) otherwise. Conclusion -A high index of suspicion is important to diagnose and treat such cases early to avoid lethal outcomes by misdiagnosing it as simple rectal prolapse. [ABSTRACT FROM AUTHOR]

Highlights • Castleman disease: heterogeneous group of hyperimmune lymphoproliferative disorders. • Unicentric type: localized disease; surgery is primary treatment; good prognosis. • Multicentric type: Serious systemic disease; 70% linked to HHV8; antiviral therapy. • Idiopathic Multicentric type: diagnosis by exclusion; Interleukin-6 blockade useful. Abstract Castleman Disease (CD) is a rare, heterogeneous group of hyperimmune lymphoproliferative disorders, not very familiar to surgeons. Unicentric Castleman Disease (UCCD) at one end of the spectrum is a localized disease, with little or no systemic symptoms. It may be an incidental radiological finding or detected while investigating for a symptomatic lymph node mass. Surgery is the primary treatment and has good long term prognosis. Multicentric Castleman Disease (MCCD) is a more serious systemic condition, often associated with constitutional symptoms. Exaggerated systemic inflammatory response secondary to "Cytokine storm" involving Interleukin-6 (IL-6) may cause multi-organ dysfunction. In addition, immunosuppression or malignant transformation can prove lethal. Human Herpes Simplex Virus 8 (HHV8) associated MCCD is a major subgroup occurring in immunocompromised individuals due to the viral trigger. Antiviral therapy is important in its treatment. Idiopathic MCCD (IMCCD) has no known biomarker and is diagnosed after excluding infective, autoimmune and malignant conditions of lymphoid tissue. IMCCD requires systemic therapy. We report a patient of UCCD who presented as a retroperitoneal mass in right iliac fossa causing pressure on femoral nerve. Following successful surgical excision she had good recovery. We report another patient who had large inguinal lymph node mass with constitutional symptoms. IMCCD was diagnosed after excision biopsy and comprehensive work up. Patient was started on corticosteroids followed by CD-20 targeted therapy. These two cases showcase the two ends of the clinical spectrum of CD requiring different management protocols. Awareness among surgeons and diligent work-up is imperative for early diagnosis and best outcome. [ABSTRACT FROM AUTHOR]