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Melanoma is the deadliest malignancy of the skin with an estimated 91 000 new annual cases with 9300 deaths in 2018. Metastatic disease generally presents with identification of known primary lesion; however, in 3.2% of patients, metastatic disease is discovered with unknown primary lesion/site. Rarely, melanoma is diagnosed as a primary lesion in visceral organs. Suspected primary hepatic melanoma is exceedingly rare and described in only a few case reports. We present the case of a 69-year-old Caucasian male who was found to have a hepatic melanoma on final pathology after resection of suspected primary hepatic malignancy. After a thorough postoperative workup, a primary lesion was unable to be identified. As such, a visceral primary lesion is considered.

Adrenocortical carcinoma (ACC) is rare within the adult population. Ectopic ACC proves even rarer. This variant is formed by cortical fragments arrested during embryologic migration. ACC is also known to be associated with several genetic syndromes and has recently been linked to Lynch syndrome in 3% of cases. We present the case of a 68-year-old male with a confirmed diagnosis of Lynch syndrome secondary to a germline MSH2 mismatch-repair gene-mutation who presented with 2 months history of non-specific abdominal pain. After imaging work-up, the patient was found to have a right upper quadrant, retroperitoneal mass. Biochemical tests were without any evidence of a hormonally active process. Fine needle aspiration of the mass revealed a poorly differentiated carcinoma of unknown etiology. The lesion was resected and found to be consistent with ectopic ACC with an associated MSH2 mutation.

Long noncoding RNAs are investigated using a CRISPR–Cas9 activation screen and shown to confer BRAF inhibitor resistance on melanoma cells through various local mechanisms. CRISPR–Cas9 screen identifies lncRNAs driving anticancer drug resistance Long non-coding RNA (lncRNA) loci are very abundant in the human genome, but identifying the functional roles of many of these regions in health and disease has been challenging. The authors developed a genome-scale CRISPR–Cas9 activation screening approach to identify lncRNA loci that influence resistance to BRAF inhibitors in melanoma cells. The screen identified several novel candidate loci with a local and distant role on gene expression. These lncRNA loci include EMICERI , which controls the activation of genes that drive resistance to vemurafenib, a clinically approved therapy for late-stage melanoma. Mammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs) 1 , 2 , some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms 3 , 4 , 5 , 6 , 7 , 8 . Although some lncRNA loci encode RNAs that act non-locally (in trans ) 5 , there is emerging evidence that many lncRNA loci act locally (in cis ) to regulate the expression of nearby genes—for example, through functions of the lncRNA promoter, transcription, or transcript itself 3 , 6 , 7 , 8 . Despite their potentially important roles, it remains challenging to identify functional lncRNA loci and distinguish among these and other mechanisms. Here, to address these challenges, we developed a genome-scale CRISPR–Cas9 activation screen that targets more than 10,000 lncRNA transcriptional start sites to identify noncoding loci that influence a phenotype of interest. We found 11 lncRNA loci that, upon recruitment of an activator, mediate resistance to BRAF inhibitors in human melanoma cells. Most candidate loci appear to regulate nearby genes. Detailed analysis of one candidate, termed EMICERI , revealed that its transcriptional activation resulted in dosage-dependent activation of four neighbouring protein-coding genes, one of which confers the resistance phenotype. Our screening and characterization approach provides a CRISPR toolkit with which to systematically discover the functions of noncoding loci and elucidate their diverse roles in gene regulation and cellular function.

Early recognition and management of hemorrhage, damage control resuscitation, and blood product administration have optimized management of severe trauma. Recent data suggest hypocalcemia exacerbates the ensuing effects of coagulopathy in trauma. This narrative review of available literature describes the physiology and role of calcium in trauma resuscitation. Authors did not perform a systematic review or meta-analysis. Calcium is a divalent cation found in various physiologic forms, specifically the bound, inactive state and the unbound, physiologically active state. While calcium plays several important physiologic roles in multiple organ systems, the negative hemodynamic effects of hypocalcemia are crucial to address in trauma patients. The negative ramifications of hypocalcemia are intrinsically linked to components of the lethal triad of acidosis, coagulopathy, and hypothermia. Hypocalcemia has direct and indirect effects on each portion of the lethal triad, supporting calcium's potential position as a fourth component in this proposed lethal diamond. Trauma patients often present hypocalcemic in the setting of severe hemorrhage secondary to trauma, which can be worsened by necessary transfusion and resuscitation. The critical consequences of hypocalcemia in the trauma patient have been repeatedly demonstrated with the associated morbidity and mortality. It remains poorly defined when to administer calcium, though current data suggest that earlier administration may be advantageous. Calcium is a key component of trauma resuscitation and the coagulation cascade. Recent data portray the intricate physiologic reverberations of hypocalcemia in the traumatically injured patient; however, future research is needed to further guide the management of these patients.

Introduction: There is growing evidence that computer-delivered or computer-assisted forms of cognitive behavior therapy (CCBT) are helpful, but cost-effectiveness versus standard therapies is not well established. Objective: To evaluate the cost-effectiveness of a therapist-supported method for CCBT in comparison to standard cognitive behavior therapy (CBT). Methods: A total of 154 drug-free major depressive disorder outpatients were randomly assigned to either 16 weeks of standard CBT (up to twenty 50-min sessions) or CCBT using the Good Days Ahead program (including up to 5.5 h of therapist contact). Outcomes were assessed at baseline, weeks 8 and 16, and at 3 and 6 months post-treatment. Economic analyses took into account the costs of services received and work/social role impairment. Results: In the context of almost identical efficacy, a form of CCBT that used only about one third the amount of therapist contact as conventional CBT was highly cost-effective compared to conventional therapy and reduced the adjusted cost of treatment by USD 945 per patient. Conclusions: A method of CCBT that blended internet-delivered modules and abbreviated therapeutic contact reduced the cost of treatment substantially without adversely affecting outcomes. Results suggest that use of this approach can more than double the access to CBT. Because clinician support in CCBT can be provided by telephone, videoconference, and/or email, this highly efficient form of treatment could be a major advance in remote treatment delivery.

The staphylococcal virulon is controlled largely by the agr locus, a global accessory gene regulator that is autoinduced by a self-coded peptide (AIP) and is therefore a quorum sensor. The agr locus has diverged within and between species, giving rise to AIP variants that inhibit heterologous agr activation, an effect with therapeutic potential against Staphylococcus aureus: a single dose of an inhibitory AIP blocks the formation of an experimental murine abscess. As the AIP is unstable at physiological pH, owing to its essential thiolactone bond, its single-dose efficacy seems paradoxical, which has led us to analyze the in vivo kinetics of agr activation and the consequences of its blockage by a heterologous AIP. Initially, the infecting bacteria grow rapidly, achieving sufficient population density within the first 3 h to activate agr, and then enter a neutrophil-induced metabolic eclipse lasting for 2-3 d, followed by agr reactivation concomitantly with the development of the abscess. The inhibitory AIP prevents agr expression only during its short in vivo lifetime, suggesting that the agr-induced and therefore quorum-dependent synthesis of virulence factors shortly after infection is necessary for the subsequent development of the abscess lesion and bacterial survival. We confirm this finding by showing that a sterile agr+supernatant causes a sterile abscess similar to the septic abscess caused by live bacteria. These results may provide a biological rationale for regulation of virulence factor expression by quorum sensing rather than by response to specific host signals.