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Author(s): Si Hui Tan [sup.1] , Yada Swathi [sup.1] , Shawna Tan [sup.1] , Jasmine Goh [sup.1] , Ryo Seishima [sup.1] , Kazuhiro Murakami [sup.2] , Masanobu Oshima [sup.3] , [...], LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach.sup.1, but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5.sup.+ intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway.sup.2. However, the contribution of pyloric LGR5.sup.+ stem cells to gastric cancer following dysregulation of the WNT pathway--a frequent event in gastric cancer in humans.sup.3--is unknown. Here we use comparative profiling of LGR5.sup.+ stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5.sup.+ compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5.sup.+ cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic. AQP5 is identified as a marker for pyloric stem cells in humans and mice, and stem cells in the AQP5.sup.+ compartment are shown to be a source of invasive gastric cancer in mouse models.

Although combination therapy is the standard of care for relapsed/refractory non-Hodgkin's lymphoma (RR-NHL), combination treatment chosen for an individual patient is empirical, and response rates remain poor in individuals with chemotherapy-resistant disease. Here, we evaluate an experimental-analytic method, quadratic phenotypic optimization platform (QPOP), for prediction of patient-specific drug combination efficacy from a limited quantity of biopsied tumor samples. In this prospective study, we enrolled 71 patients with RR-NHL (39 B cell NHL and 32 NK/T cell NHL) with a median of two prior lines of treatment, at two academic hospitals in Singapore from November 2017 to August 2021. Fresh biopsies underwent ex vivo testing using a panel of 12 drugs with known efficacy against NHL to identify effective single and combination treatments. Individualized QPOP reports were generated for 67 of 75 patient samples, with a median turnaround time of 6 days from sample collection to report generation. Doublet drug combinations containing copanlisib or romidepsin were most effective against B cell NHL and NK/T cell NHL samples, respectively. Off-label QPOP-guided therapy offered at physician discretion in the absence of standard options (n = 17) resulted in five complete responses. Among patients with more than two prior lines of therapy, the rates of progressive disease were lower with QPOP-guided treatments than with conventional chemotherapy. Overall, this study shows that the identification of patient-specific drug combinations through ex vivo analysis was achievable for RR-NHL in a clinically applicable time frame. These data provide the basis for a prospective clinical trial evaluating ex vivo–guided combination therapy in RR-NHL. Predicting possibilities with PDXs: Patients with non-Hodgkin's lymphomas (NHLs) often relapse after frontline treatment, and interpatient heterogeneity make personalized combination treatment difficult. Goh et al. have developed a hybrid experimental-analytic method that they call quadratic phenotypic optimization platform, or QPOP, to identify personalized drug combination therapies using ex vivo patient samples to improve patient outcomes. In a prospective cohort, physicians were able to alter treatment according to drug combinations identified using QPOP after 6 days to achieve complete responses in 5 of 17 patients with NHL. This is a promising step for providing new hope for patients who have relapsed NHL and provides a foundation for further clinical trials. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p <.001) was found for TS versus general population controls and 0.925 (p <.001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome. [ABSTRACT FROM AUTHOR]

Background: Enzyme replacement therapy significantly reduces morbidity and mortality in patients with Pompe disease. Development of hypersensitivity reactions to enzyme replacement therapy is common and can adversely affect disease outcomes when treatment is halted or delayed., Objective: Our institution reports a case of successful alglucosidase alfa enzyme replacement therapy desensitisation in a 9-year-old girl with infantile onset Pompe disease., Methods: A desensitisation protocol was tailored to our patient with the help of a multidisciplinary team including the allergist, geneticist, nurses and pharmacists., Results: For our patient, desensitisation was successful using a multi-step three-fold dose escalation protocol., Conclusions: Desensitisation is possible in individuals with hypersensitivity reactions to enzyme replacement. Desensitisation protocols need to be tailored according to the patient's needs and responses to find a protocol that is safe, effective and simple.