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The article discusses whether the salt substitutes are safe or not. It presents a case study of a 55-year-old lady with hyperkalemia were it was found that she use to intake low sodium salt substitute. She was treated with anti-hyperkalemic measures and her symptoms were resolved completely after correction of hyperkalemia. It proposes that the use of "low salt" substitutes without the awareness of its potential life threatening side effects may develop hyperkalemia.

Purpose: Biliary tract cancers (BTCs), which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant BTC models which recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in BTCs to create a resource for modeling precision oncology., Experimental Design: PDXs were derived from BTC collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were identified by whole exome sequencing and RNASeq. PDXs were treated with approved and investigational agents. Efficacy was assessed by change in tumor volume from baseline. Event-free survival was defined as time to tumor doubling from baseline. Responses were categorized at day 21: >30% decrease=partial response; >20% increase in tumor volume=progressive disease, and any non-PR/PD was considered stable disease., Results: Genomic sequencing demonstrated key actionable alterations across this cohort, including alterations in FGFR2, IDH1, ERRB2, PIK3CA, PTEN and KRAS. RNAseq demonstrated fusions and expression of antibody drug conjugate targets including TROP2, HER2 and Nectin4. Therapeutic matching revealed objective responses to approved and investigational agents that have been shown to have antitumor activity clinically., Conclusions: Here, we developed a catalog of BTC PDXs which underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of BTC PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.

The Wnt receptor ROR1 has generated increased interest as a cancer therapeutic target. Research on several therapeutic approaches involving this receptor is ongoing; however, ROR1 tissue expression remains understudied. We performed an immunohistochemistry analysis of ROR1 protein expression in a large cohort of multiple tumor and histologic types. We analyzed 12 anonymized multi-tumor tissue microarrays (TMAs), including mesothelioma, esophageal and upper gastrointestinal carcinomas, and uterine endometrioid carcinoma, among other tumor types. Additionally, we studied 5 different sarcoma types of TMAs and 6 patient-derived xenografts (PDX) TMAs developed from 19 different anatomic sites and tumor histologic types. A total of 1142 patient cases from different histologic types and 140 PDXs placed in TMAs were evaluated. Pathologists assessed the percentage of tumor cells in each case that were positive for ROR1 and the intensity of staining. For determining the prevalence of staining for each tumor type, a case was considered positive if >1% of its tumor cells showed ROR1 staining. Our immunohistochemistry assays revealed a heterogeneous ROR1 expression profile. A high prevalence of ROR1 expression was found in mesothelioma (84.6%), liposarcoma (36.1%), gastrointestinal stromal tumors (33.3%), and uterine endometrioid carcinoma (28.9%). Other histologic types such as breast, lung, renal cell, hepatocellular, urothelial carcinoma, and colon carcinomas; glioblastoma; cholangiocarcinoma; and leiomyosarcoma showed less ROR1 overall expression, ranging between 0.9 and 13%. No ROR1 expression was seen in mesenchymal chondrosarcoma, rhabdomyosarcoma, or gastric adenocarcinoma cases. Overall, ROR1 expression was relatively infrequent and low in most tumor types investigated; however, ROR1 expression was infrequent but high in selected tumor types, such as gastroesophageal GIST, suggesting that ROR1 prescreening may be preferable for those indications. Further, mesothelioma exhibited frequent and high levels of ROR1 expression, which represents a previously unrecognized therapeutic opportunity. These findings can contribute to the development of ROR1-targeted therapies.

Background: The study was aimed at identifying how useful Computer-Aided Detection (CAD) could be in reducing false-negative reporting in mammography and early detection of breast cancer at an early stage as the best protection is early detection., Materials and Methods: This retrospective study was conducted in a tertiary care setup of Atomic Energy Cancer Hospital, Nuclear Medicine, Oncology and Radiotherapy Institute (AECH-NORI), where 33 patients with suspicious findings on mammography and subsequent biopsy-proven malignancy were included. The findings of mammography including the lesion type, breast parenchymal density, and sensitivity of CAD detection, as well as the final biopsy results, were recorded. A second group of 40 normal screening mammograms was also included who had no symptoms, had Breast Imaging-Reporting and Data System category I(BI-RADS I) mammograms, and had no pathology identified on correlative sonomammography as well., Results: A total of 35 masses, 11 pleomorphic clusters of microcalcification, five clustered foci of macrocalcification, and nine lesions with pleomorphic clusters of microcalcification and two with pleomorphic clusters of microcalcification only were included. The CAD system was able to identify 26 masses (74%), eight lesions with pleomorphic clusters of microcalcification (72%), five foci of macrocalcification (100%), six lesions with pleomorphic clusters of microcalcification (66%), and two pleomorphic clusters of microcalcification without formed mass (100%). The overall sensitivity of the CAD system was 75.8%. CAD was able to identify 13 out of 16 masses with invasive ductal carcinoma (81.3%), eight out of nine lesions proven as invasive ductal carcinoma with ductal carcinoma in situ (DCIS) (88.9%), two out of five masses with invasive lobular carcinoma (40%), four out of four masses with invasive mammary carcinoma (100%), and zero out of one lesion identified as medullary carcinoma (0%). There was 100% detection for pleomorphic clusters of microcalcification without formed mass with CAD marking two out of two mammograms., Conclusion: CAD performed better with combined lesions, accurately marked pleomorphic clusters of microcalcification, and identified small lesions in predominant fibrofatty parenchymal density but was not reliable in dense breast, areas of asymmetric increased density, summation artifacts, edematous breast parenchyma, and retroareolar lesions. It also performed poorly with ill-defined lesions of invasive lobular carcinoma. Human intelligence hence beats CAD for the diagnosis of breast malignancy in mammograms as per our experience., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Malik et al.)

The ongoing battle against the coronavirus disease 2019 (COVID-19) pandemic has encountered a complex aspect with the emergence of long COVID syndrome. There has been a growing prevalence of COVID-19-affected individuals experiencing persistent and diverse symptoms that extend beyond the initial infection phase. The phenomenon known as long COVID syndrome raises significant questions about the underlying mechanisms driving these enduring symptoms. This comprehensive analysis explores the complex domain of long COVID syndrome with a view to shed light on the specific tissue and organ pathologies contributing to its intricate nature. This review aims to analyze the various clinical manifestations of this condition across different bodily systems and explore potential mechanisms such as viral persistence, immune dysregulation, autoimmunity, and molecular mimicry. The goal is to gain a better understanding of the intricate network of pathologies contributing to long COVID syndrome. Understanding these distinct pathological indicators provides valuable insights into comprehending the complexities of long COVID and presents opportunities for developing more accurate diagnostic and therapeutic strategies, thereby improving the quality of patient care by effectively addressing the ever-changing medical challenge in a more focused manner., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Sapna et al.)

Background: Under-reporting of clinical trial results can lead to negative consequences that include inhibiting propagation of knowledge, limiting the understanding of how devices work, affecting conclusions of meta-analyses, and failing to acknowledge patient participation. Therefore clinical trial transparency, through publication of trial results on ClinicalTrials.gov or in manuscript form, is important. We aimed to examine clinical trial transparency in endoscopic clinical trials., Methods: The ClinicalTrials.gov database was searched for endoscopy trials up to October 2019. Adherence to the reporting of results to the database or in publication form was recorded for each trial., Results: The final analysis included 923 trials, of which 801 were completed and 122 were either terminated or suspended. Results were available either on ClinicalTrials.gov or in publication for 751/923 trials (81.4 %). Other fields have reported a publication rate of 40 %-63 %. Results were available on ClinicalTrials.gov for 168 trials (18.2 %) and in the form of a publication for 720 trails (78.0 %)., Conclusions: Compared with other fields in medicine, endoscopy clinical trials have a high rate of clinical trial transparency. However, there is room for improvements as close to one-fifth of trials fail to report results and 81.8 % do not report results to ClinicalTrials.gov., Competing Interests: Arvind J. Trindade is a consultant for Pentax Medical. The remaining authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Most tumors with activating MAPK (mitogen-activated protein kinase) pathway alterations respond poorly to MEK inhibitors alone. Here, we evaluated combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 in TP53 wild-type and MAPK altered colon and thyroid cancer models. In vitro, we showed synergy between selumetinib and KRT-232 on cell proliferation and colony formation assays. Immunoblotting confirmed p53 upregulation and MEK pathway inhibition. The combination was tested in vivo in seven patient-derived xenograft (PDX) models (five colorectal carcinoma and two papillary thyroid carcinoma models) with different KRAS, BRAF, and NRAS mutations. Combination therapy significantly prolonged event-free survival compared with monotherapy in six of seven models tested. Reverse-phase protein arrays and immunohistochemistry, respectively, demonstrated upregulation of the p53 pathway and in two models cleaved caspase 3 with combination therapy. In summary, combined inhibition of MEK and MDM2 upregulated p53 expression, inhibited MAPK signaling and demonstrated greater antitumor efficacy than single drug therapy in both in vitro and in vivo settings. These findings support further clinical testing of the MEK/MDM2 inhibitor combination in tumors of epithelial origin with MAPK pathway alterations., (© 2022. The Author(s).)

Epigenetic changes that cause dysregulated gene expression during progression of androgen-independent prostate cancer (PCa) and metastatic skeletal lesions remain elusive. Here, we explored the role of histone demethylase NO66 in the pathogenesis of PCa and bone metastasis-related skeletal lesions. Tissue and cDNA microarrays of PCa were analyzed for NO66 mRNA and protein levels. We examined the effects of gain and loss of NO66 function on cell viability, colony formation, migration, invasion, and tumor-induced skeletal lesions in femoral bone. RNAseq and ChIPseq were performed to elucidate NO66-target genes in PCa. We report that NO66 levels were upregulated in advanced primary prostate tumors compared to normal tissue or tumors with low Gleason scores. Forced expression of NO66 promoted cell survival and invasion of PCa cells; whereas, knockdown of NO66 resulted in decreased cell survival and increased sensitivity to docetaxel. NO66-overexpressing PC3 cells implanted into the femoral bone of male SCID mice caused massive bone loss and stimulation of mouse osteoclast-promoting genes, including Dickkopf1, Cathepsin K, Nf-kβ,; and Calcr, suggesting a role for NO66 in tumor growth in bone and osteoclast activity. Combined RNAseq and ChIP-seq revealed that NO66 activates the survival gene MCL1, the invasion-associated genes IGFBP5 and MMP3, the pro-oncogenic genes CTNNB1 and CCND1, and the epigenetic modifier gene KMT2A in androgen-independent PCa. Our findings uncover the role of NO66 as a key oncogenic driver in PCa, causing osteolytic lesions through upstream epigenetic regulation of key genes for survival, invasion and metastasis, and pro-osteoclastic factors.

Objective: Statins are widely used drugs, known to cause myalgia, leading to high discontinuation rates. The objective of our study was to determine the frequency of myalgia in patients on everyday-dose (EDD) regimen with those on alternate-day dose (ADD) regimen., Methods: This cross sectional study was conducted in a tertiary care hospital of Pakistan. A sample size of 400 patients between the age of 40-70 years, taking simvastatin 40mg for at least 6 months or more were selected. Patients with prior musculoskeletal or neuromuscular complains, and family history of muscular disorders were excluded. Subjects were evaluated for myalgia via a self-administered questionnaire, and those complaining of myalgia were then evaluated for serum vitamin D levels. Data was analyzed through SPSS 16.0 and compared using chi square test., Results: The overall prevalence of myalgia was 7% (28/400). Frequency of myalgia in patients taking simvastatin everyday (n=20, 10%) was significantly higher compared to those taking it every alternate day (n=8, 4%) (p=0.02). There was no significant difference between the time of onset, nature, severity, type, or location of myalgia between the 2 groups. The most common cited triggering factor for pain was physical exercise. Of the patients experiencing myalgia, 13 (6.5%) from the EDD group and 6 (3%) from the ADD group had low levels of vitamin D., Conclusions: ADD regime was better tolerated by the patients than EDD regime. Alternate day therapy, with or without vitamin D supplementation, may be used by the physicians for troublesome muscular complains., (Copyright © 2017. Published by Elsevier B.V.)

Muscle proteolysis in CKD is stimulated when the ubiquitin-proteasome system is activated. Serum glucocorticoid-regulated kinase 1 (SGK-1) is involved in skeletal muscle homeostasis, but the role of this protein in CKD-induced muscle wasting is unknown. We found that, compared with muscles from healthy controls, muscles from patients and mice with CKD express low levels of SGK-1. In mice, SGK-1-knockout (SGK-1-KO) induced muscle loss that correlated with increased expression of ubiquitin E3 ligases known to facilitate protein degradation by the ubiquitin-proteasome, and CKD substantially aggravated this response. SGK-1-KO also altered the phosphorylation levels of transcription factors FoxO3a and Smad2/3. In C2C12 muscle cells, expression of dominant negative FoxO3a or knockdown of Smad2/3 suppressed the upregulation of E3 ligases induced by loss of SGK-1. Additionally, SGK-1 overexpression increased the level of phosphorylated N-myc downstream-regulated gene 1 protein, which directly interacted with and suppressed the phosphorylation of Smad2/3. Overexpression of SGK-1 in wild-type mice with CKD had similar effects on the phosphorylation of FoxO3a and Smad2/3 and prevented CKD-induced muscle atrophy. Finally, mechanical stretch of C2C12 muscle cells or treadmill running of wild-type mice with CKD stimulated SGK-1 production, and treadmill running inhibited proteolysis in muscle. These protective responses were absent in SGK-1-KO mice. Thus, SGK-1 could be a mechanical sensor that mediates exercise-induced improvement in muscle wasting stimulated by CKD., (Copyright © 2016 by the American Society of Nephrology.)

A young adult was diagnosed to have acute lymphoblastic leukemia, T-cell immunophenotype and was initiated on chemotherapy. He presented with acute renal failure two days after the completion of his induction regimen. A renal biopsy showed features of necrotizing crescentic glomerulonephritis (GN). Serology for c-anti-neutrophil cytoplasmic antibody (ANCA) was positive and a final diagnosis of ANCA-associated necrotizing crescentic GN was made. Aggressive immunosuppression could not be used due to the presence of nosocomial pneumonia and the patient expired 26 days after the renal biopsy diagnosis. We report for the first time the association of acute lymphoblastic leukemia with crescentic GN and, hence, expand the list of malignancy-related ANCA-positive GN.