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Supplementary Figure 1 from All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis

Supplementary Figure 3 from All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis

Supplementary Figure 2 from All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis

While heart disease remains a common cause of mortality, cerebrovascular disease also increases with age, and has been implicated in Alzheimer's disease and related dementias (ADRD). We have described hydrogen sulfide (H2S), a signaling molecule important in vascular homeostasis, as a biomarker of cardiovascular disease. We hypothesize that plasma H2S and its metabolites also relate to vascular and cognitive dysfunction in ADRD. We used analytical biochemical methods to measure plasma H2S metabolites and MRI to evaluate indicators of microvascular disease in ADRD. Levels of total H2S and specific metabolites were increased in ADRD versus controls. Cognition and microvascular disease indices were correlated with H2S levels. Total plasma sulfide was the strongest indicator of ADRD, and partially drove the relationship between cognitive dysfunction and white matter lesion volume, an indicator of microvascular disease. Our findings show that H2S is dysregulated in dementia, providing a potential biomarker for diagnosis and intervention., Scheme for sulfide dysregulation in ADRD. In ADRD, increased accumulation of sulfides, measured in plasma, may reflect increased formation of H2S metabolites produced in the vascular compartment. Several sulfide species are known to impair blood brain barrier leading to persistent excitotoxic stress and subsequent destructive changes in brain microvascular structure and cognitive function seen in ADRD.

Thyroid status has not been studied well in children with steroid resistant nephrotic syndrome (SRNS). In this cross sectional study we recruited 20 children aged 1–16 years with SRNS and similar number of controls. Serum levels of FT3, FT4 and TSH were measured in all the subjects. Overt hypothyroidism was defined as low FT4 (normal values: 0.7–2.0 ng/mL) and elevated serum TSH above reference values (0.45–4.5 mIU/L). Subclinical hypothyroidism (SH) was defined as an elevation in serum TSH with a normal serum FT4 concentration. The primary outcome measure was serum levels of FT3, FT4 and TSH in children with SRNS. Thirty per cent of the children (n = 6) with SRNS had non-autoimmune subclinical hypothyroidism (2 children each with grade I, II and III). Children with SRNS had a median TSH value [3.9 mIU/L (0.5–13)] within normal range, but levels were high as compared to controls. Out of 6 children with SH, 3 were in partial remission, 3 were in complete remission. The TSH levels normalized on thyroxine supplementation in grades II and III subclinical hypothyroidism. Subclinical non-autoimmune hypothyroidism is present in a significant proportion of children with SRNS despite partial or complete remission. Thyroid profile should be evaluated routinely in this subset of patients.

OBJECTIVE There is increasing interest in neuromodulation for addiction. Methamphetamine abuse is a global health epidemic with no proven treatment. The objective of this study was to examine the effects of intermittent nucleus accumbens shell (AcbSh) deep brain stimulation (DBS) on operant methamphetamine intake and on methamphetamine seeking when stimulation is delivered in an environment different from that of drug use. METHODS Eighteen rats were implanted with intravenous (IV) catheters and bilateral AcbSh electrodes and subsequently underwent daily sessions in 2-lever (active/methamphetamine and inactive/no reward) operant chambers to establish IV methamphetamine self-administration. After stable responding was achieved, 3 hours of DBS or sham treatment was administered (sham: 0 µA, n = 8; active: 200 µA, n = 10) in a separate nondrug environment prior to the daily operant sessions for 5 consecutive days. Immediately following each DBS/sham treatment, rats were placed in the operant chambers to examine the effects of remote stimulation on methamphetamine intake. After the 5 days of therapy were finished, rats reestablished a posttreatment baseline, followed by extinction training, abstinence, and 1 day of relapse testing to assess methamphetamine-seeking behavior. RESULTS There was a decrease in total methamphetamine intake in rats receiving active DBS versus sham on Days 1 (42%) and 2 (44%). Methamphetamine administration returned to baseline levels following the cessation of DBS therapy. Compared with baseline drug responding, methamphetamine seeking was reduced (57%) in the DBS group but not in the sham group. CONCLUSIONS It is feasible to deliver noncontinuous DBS outside of the drug use environment with a resultant decrease in IV methamphetamine intake and seeking. The AcbSh is a neuroanatomical substrate for psychostimulant reinforcement and may be a target for intermittent neuromodulatory therapies that could be administered during brief periods of sobriety.

Squamous cell carcinoma (SCC) of the skin is the most clinically aggressive form of nonmelanoma skin cancer. We have determined the effects of all-trans retinoic acid (ATRA), a naturally occurring chemopreventive retinoid, on signal transducer and activator of transcription 3 (Stat3) signaling during the development of skin SCC. Stat3 is a transcription factor that plays a critical role in cell proliferation and survival, and it is constitutively active in several malignant cell types. We have previously shown that Stat3 is required for the initiation, promotion, and progression of skin SCC. ATRA is a highly efficient suppressor of tumor formation in the two-stage mouse skin carcinogenesis model and we have shown that this effect correlates with the suppression of the B-Raf/Mek/Erk signaling pathway. In this study, we have determined the pattern of Stat3 phosphorylation throughout the course of the two-stage protocol, both in the presence and absence of ATRA. We have used both SENCAR mice and K5.Stat3C transgenic mice, which express the Stat3C protein, a constitutively active form of Stat3, in the skin. Using Western blotting and immunohistochemical staining with phosphospecific antibodies, we show that coadministration of ATRA suppressed the 12-O-tetradecanoylphorbol-13-acetate–induced phosphorylation of Stat3 in both models, but was only able to suppress tumor formation in the SENCAR mice. Surprisingly, ATRA actually enhanced tumor formation in 12-O-tetradecanoylphorbol-13-acetate–treated K5.Stat3C mice. We hypothesize that ATRA blocks tumor formation, at least in part, by targeting events upstream of Stat3, such as the B-Raf/Mek/Erk pathway, and that in the K5.Stat3C mice, in which Stat3 activity is constitutive, it cannot suppress tumor formation.

Substance use disorders, particularly to methamphetamine, are devastating, relapsing diseases that disproportionally affect young people. There is a need for novel, effective and practical treatment strategies that are validated in animal models. Neuromodulation, including deep brain stimulation (DBS) therapy, refers to the use of electricity to influence pathological neuronal activity and has shown promise for psychiatric disorders, including drug dependence. DBS in clinical practice involves the continuous delivery of stimulation into brain structures using an implantable pacemaker-like system that is programmed externally by a physician to alleviate symptoms. This treatment will be limited in methamphetamine users due to challenging psychosocial situations. Electrical treatments that can be delivered intermittently, non-invasively and remotely from the drug-use setting will be more realistic. This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence. Methamphetamine dependence is rapidly developed in rodents using an operant paradigm of intravenous (IV) self-administration that incorporates a period of extended access to drug and demonstrates both escalation of use and high motivation to obtain drug.

This case report describes ruphus arthropathy in a 13-year-old girl with systemic lupus erythematosus. A detailed case description is given, together with laboratory results. Subcutaneous nodules were present on distal interphalangeal joints of the hands and fixed flexion deformity was present at metacarpophalangeal, proximal interphalangeal and distal interphalangeal joints of the fifth digit. Anticyclic citrullinated peptide antibody (antibodies against cyclic citrullinated peptides) titers were 79 U/ml (normal: 5 U/ml), a specific marker for rheumatoid arthritis. Renal biopsy was confirmatory of lupus nephritis. A diagnosis of childhood-onset systemic lupus erythematosus was made according to the modified ACR criteria. Clinicians need to be careful in monitoring the serious manifestations of the disease in childhood-onset lupus patients with rhupus arthropathy, and consider the poor response to standard disease-modifying agents.

Background Homocysteine metabolism is altered in children with idiopathic nephrotic syndrome. Hyperhomocysteinemia is a risk factor of early atherosclerosis and glomerulosclerosis and may occur at time of first occurrence of idiopathic nephrotic syndrome. Methods Thirty children with first episode of idiopathic nephrotic syndrome (FENS) aged 1–16 years along with 30 age- and sex-matched healthy controls were enrolled in this study. Homocysteine and cysteine were measured with HPLC; vitamin B12 and folic acid were measured with electro-chemilumiscence immunoassay. Primary outcome measure was plasma homocysteine level in children with FENS and in controls. Secondary outcome measures were (1) plasma and urine homocysteine and cysteine levels in children with FENS at 12 weeks and 1 year (remission) and (2) plasma and urine levels of vitamin B12 and folic acid in children with FENS, at 12 weeks and 1 year (remission). Results Plasma homocysteine and cysteine levels were comparable to controls in children with FENS, at 12 weeks and 1-year remission. Plasma levels of vitamin B12 and folic acid were significantly decreased compared to controls in FENS due to increased urinary excretion, which normalize during remission at 12 weeks and 1 year. Urinary homocysteine and cysteine levels were significantly raised in FENS compared to controls and continued to be raised even at 12-week and 1-year remission. Conclusion Homocysteine metabolism is deranged in children with FENS. Renal effects of long-term raised urinary homocysteine levels need to be studied.

Impaired endothelial function is the initial step in atherogenesis, which is largely responsible for ischaemic heart disease and thrombotic strokes decades later.Fourty two children with first episode nephrotic syndrome (FENS) aged 1-16 years and 40 controls were enrolled. Soluble thrombomodulin (sTM), tissue plasminogen activator (t-PA), plasminogen activator inhibitor -1 (PAI-1) and von-willebrand factor (vWF) levels were measured in plasma in FENS, at 12 weeks of drug induced remission and in steroid resistant nephrotic syndrome (SRNS) patients at diagnosis.PAI-1, sTM, vWF and t-PA were significantly raised at the onset of nephrotic syndrome (p0.0001). All the markers had a fall after 12 weeks of steroid treatment, but were still raised. Children with SRNS had higher levels of sTM, tPA, vWF as compared to infrequent relapsers, at onset and at 4 weeks of steroid treatment.Children with idiopathic nephrotic syndrome have endothelial dysfunction which is largely dependent upon disease activity.

The purpose of the current study was to determine whether a tropical ginger derived compound 1’-acetoxychavicol acetate (ACA), suppresses skin tumor promotion in K5.Stat3C mice. In a two-week study in which wild-type (WT) and K5.Stat3C mice were co-treated with either vehicle, ACA, galanga extract, or fluocinolone acetonide (FA) and tetradecanoyl phorbol acetate (TPA), only the galanga extract and FA suppressed TPA-induced skin hyperproliferation and wet weight. None of these agents were effective at suppressing p-Tyr705Stat3 expression. However, ACA and FA showed promising inhibitory effects against skin tumorigenesis in K5.Stat3C mice. ACA also suppressed phospho-p65 NF-κB activation, suggesting a potential mechanism for its action.

A new cytoplasmic male-sterility system was developed in an oilseed Brassica, viz. B. juncea var. 'Pusa Bold' with the cytoplasmic background of a wild species, Diplotaxis siifolia, obtained through wide hybridization. The synthetic alloploid (D. siifolia×B. juncea: 2n=56, D 3 D 3 AABB) was repeatedly backcrossed to B. juncea to achieve cytoplasmic substitution. The CMS plants resembled the cultivar in growth and morphology. The flowers had narrow sepals and petals and short, shrivelled anthers which failed to dehisce. The meiotic process appeared to be normal. The microspores degenerated at an early stage after tetrad formation. Female fertility in the CMS plants was as good as in the cultivar. Female transmission of sterility confirmed it to be cytoplasmically encoded.

Oxycodone, a semisynthetic opioid analgesic, is frequently prescribed for the management of pain. Side effects of nausea and emesis affect patient compliance and limit its therapeutic use. The present study established that an antinociceptive dose of oxycodone (15 mg/kg; oral) induces the pica response. We found sex differences in the temporal course of pica, with females having a longer duration. Opioid receptors mediated the pica response, as 1.0 mg/kg naloxone transiently attenuated and 2.0 mg/kg naloxone blocked pica. A κ-selective antagonist failed to block the response, suggesting mediation by μ opioid receptor. For further validation, we used the well established kaolin intake model to assess pica with the chemotherapeutic drug cisplatin as a positive control. Oxycodone and cisplatin significantly increased kaolin intake 4- to 7-fold, and the wet weight of stomach was elevated 2- to 3-fold. To examine the underlying neural circuitry, we investigated c-fos activation in the area postrema and nucleus of solitary tract (NTS). Oxycodone treatment significantly increased the number of c-fos-positive neurons in the area postrema and NTS compared with water controls. As expected, cisplatin also increased the number of c-fos-positive cells in these regions. In the area postrema, the oxycodone effect was greater than cisplatin, especially at 2 h. These results indicate that an antinociceptive dose of oxycodone is associated with the expression of pica, a pro-emetic response.

We present a rare case of membranoproliferative glomerulonephritis (MPGN) associated with autoimmune hypothyroidism in a child. The exact pathogenesis of glomerulonephritis remains unclear. Thyroxine replacement therapy along with steroids may lead to significant decrease in proteinuria and resolution of edema. Thyroid status should be evaluated in all cases with MPGN.

The original version of this article unfortunately contained errors. In the ‘‘Methods’’ section of the main text, under the heading ‘‘Participants’’, the sentences that begin with ‘‘Remission’’ and ‘‘No response’’ should read: Remission was defined as complete (Up/Uc \0.2 mg/ mg) or partial (Up/Uc between 0.2 and 2 mg/mg, serum albumin [2.5 g/dL, and no edema). No response was the presence of nephrotic range proteinuria (Up/Uc [2 mg/ mg), serum albumin \2.5 g/dL, or edema. In Table 2, in the first column, for the line ‘‘Spot Up/ Uc’’, the unit should be ‘‘mg/mg’’. In Table 3, in the first column, for the line ‘‘Total duration of illness (years)’’, the value of SRNS without subclinical hypothyroidism, and the unit for the line ‘‘Cumulative dose of prednisolone’’ were shown incorrectly. The corrected tables are as follows

D-dimer test is used as a diagnosis test for acute disseminated intravascular coagulation (DIC). This study was undertaken to find out its sensitivity and specificity in the diagnosis of acute DIC and its role in diagnosis of sub-clinical DIC, as there is limited data available on the subject. Of the 29 patients of clinically acute DIC, all had positive D-dimer test, and markedly prolonged PT, APTT and TT were seen in 24 (83%) of these patients. D-dimer test was found to be highly specific but less sensitive for the diagnosis of acute DIC. Of the 29 patients predisposed to sub-clinical DIC. D-dimer was positive is 26 (90%) patients and PT, APTT and TT were mildly prolonged in 11 patients. It is suggested that D-dimer positivity for the diagnoses of sub-clinical DIC need to be considered with caution and to be supplemented by other coagulation test including serial follow up with d-dimer and coagulation tests.