Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, as an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients.

Background and Objectives: Linear IgA disease (LAD) is a rare autoimmune blistering disease with linear IgA deposits along the basement membrane zone. Direct immunofluorescence remains the gold standard for diagnosis, but other diagnostic measures reported in recent literature have proven useful in the setting of inconclusive preliminary results. Dapsone is a commonly used treatment, but many therapeutic agents have emerged in recent years. The objective of this study is to provide a comprehensive overview of updates on the diagnosis and management of LAD. Materials and Methods: A literature search was conducted from May to June of 2021 for articles published in the last 5 years that were related to the diagnosis and management of LAD. Results: False-negative results in cases of drug-induced LAD and the presence of IgG and IgM antibodies on immunofluorescence studies were reported. Serration pattern analysis has been reported to be useful in distinguishing LAD from sublamina densa-type LAD. Rituximab, omalizumab, etanercept, IVIg, sulfonamides, topical corticosteroids, and others have been used successfully in adult and pediatric patients with varying disease severity. Topical corticosteroids were preferred for pediatric patients while rituximab and IVIg were used in adults with recalcitrant LAD. Sulfonamides were utilized in places without access to dapsone. Conclusion: In cases where preliminary biopsy results are negative and clinical suspicion is high, repeat biopsy and additional diagnostic studies should be used. Patient factors such as age, medical comorbidities, and disease severity play a role in therapeutic selection.

G0/G1 switch gene 2 (G0S2) is a direct retinoic acid target implicated in cancer biology and therapy based on frequent methylation-mediated silencing in diverse solid tumors. We recently reported that low G0S2 expression in breast cancer, particularly estrogen receptor-positive (ER+) breast cancer, correlates with increased rates of recurrence, indicating that G0S2 plays a role in breast cancer progression. However, the function(s) and mechanism(s) of G0S2 tumor suppression remain unclear. In order to determine potential mechanisms of G0S2 anti-oncogenic activity, we performed genome-wide expression analysis that revealed an enrichment of gene signatures related to PI3K/mTOR pathway activation in G0S2 null cells as compared to G0S2 wild-type cells. G0S2 null cells also exhibited a dramatic decreased sensitivity to PI3K/mTOR pathway inhibitors. Conversely, restoring G0S2 expression in human ER+ breast cancer cells decreased basal mTOR signaling and sensitized the cells to pharmacologic mTOR pathway inhibitors. Notably, we provide evidence here that the increase in recurrence seen with low G0S2 expression is especially prominent in patients who have undergone antiestrogen therapy. Further, ER+ breast cancer cells with restored G0S2 expression had a relative increased sensitivity to tamoxifen. These findings reveal that in breast cancer G0S2 functions as a tumor suppressor in part by repressing PI3K/mTOR activity, and that G0S2 enhances therapeutic responses to PI3K/mTOR inhibitors. Recent studies implicate hyperactivation of PI3K/mTOR signaling as promoting resistance to antiestrogen therapies in ER+ breast cancer. Our data establishes G0S2 as opposing this form of antiestrogen resistance. This promotes further investigation of the role of G0S2 as an antineoplastic breast cancer target and a biomarker for recurrence and therapy response.

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. Bilirubin increases latencies and reduces amplitudes in the auditory brainstem response (ABR). However, the basic mechanisms involved sre not known. The aim of the present study was to investigate the neurotoxic effects of bilirubin on synaptic transmission in an in vitro system. Hippocampal slices were prepared from 5-7 weeks old male Sprague-Dawley rats and incubated at 30-33'~ in an artificial cerebrospinal fluid equilibrated with 95% 0 and 5% CO to pH 7.4. We stimulated the Schaffer collaterals of th2 CA3 cells? Recordings were trade 3f the amplitudes of the presynaptic fibre volley (PV) and the field sxcitatory postsynaptic potential (EPSP) in the apical dendritic layer 3f the CAI region, and of the population spike (PS) in the corresponding cell body layer. The slices were exposed to bilirubin at >oncentrations up to ImM, in an 8:l molar ratio with bovine serum albumin (BSA). Over periods of 30-120 minutes a gradual reduction in the field EPSP amplitude was noted. In parallel with this the peak Latency of the PS increased. The stimulusfresponse relationships were sxamined with stimulus voltage from 1.0 to 3.4V. Bilirubin caused the 5VfEPSP curve to shift to the right, while the EPSPfPS curve shifted to the left. These changes were reversed when bilirubin was removed 2rom the perfusion fluid. The effect of bilirubin on rat hippocampal slices consists of a gradual and reversible decrease in synaptic transmission. This is consistent with the findings reported from ABR studies. The first child of consanguineous parents died at the age of 6 months i n renal failure due to oxalosis despite treatment with pyridoxine since the age of 4 months. rhe 3rd child of this family was found to have hyperoxalria type I at the age of 3 weeks:plasma oxalate 6 0 umol/l (n:3-23) ,plasma glycollate 1157 umol/l (n:7-33) ,urikary 2xalate 1650 mmol/rnol creat. We report on a male Turkish neonate of 38w gestation with a birthweight of 2500 g. After normal adaptation, clinical and radiological signs of cardiomegaly were noticed on the 2nd day in the absence of muscular hypotonia. Echocardiography revealed hypertrophy involving minly the right ventricle (RV) and the septum but less the left ventricle: RV anterior wall diameter and septum thicknesss were 6.0 and 6.5 mm, resp. (normal R 2 SD 2.0 2 0.3 and 2.5 t 0.4, resp.) on days two and seven. Serum C levels were low on day two (total C 15, free C 6.5 umol/l, resp.; normal: 36 -62 and 21 -56, resp). Oral substitution with L-carnitin (100 mglkg bwlday) was given from day 7 to 28. Cardiomegaly, echocardiographic parameters and serum C normalized within 10 days and remained normal for the following 3 mos. Since placental C transfer is a passive process we considered C deficiency in his mother. Four weeks after delivery, her serum C was 20 and 12 pmol/l, the muscle tone was normal, ketogenesis unimpaired and urinary excretion of dicarbonic acids absent. Excessive renal loss was ruled out (tubular reabsorption >99 5 ) . However, a low alimentary intake due to a self-imposed exclusion of ...

SD, standard deviation; y, years. a Values do not add up to the total number of participants because of missing data.

We report a case of isolated patchy red hair heterochromia of the scalp in a healthy 6‐year‐old boy. Isolated patchy scalp hair heterochromia is the presence of two or more colors of hair in the same individual, thought to be due to genetic mosaicism although no specific etiology has been widely accepted. We have outlined a basic approach to diagnosing different types of heterochromia for clinical application.