Search

Type 2 diabetes mellitus (T2DM) and cancer share common risk factors including obesity, inflammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate the PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and anti-apoptosis. The inhibition of the PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy; however, drug resistance poses a major problem in clinical settings resulting in limited efficacy of agents; thus, combination treatments with therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management.

Contributing reviewers We and the Editorial Board acknowledge and thank all reviewers for their active participation and contribution during 2012. We greatly appreciate their dedication and behind the scenes contribution. It is largely due to their support and expertise that we have been able to publish high-standard manuscripts. We would also like to thank authors for choosing Nutrition & Metabolism and contributing their cherished work.

Background: SARS-Co-V2 infection can induce ER stress-associated activation of unfolded protein response (UPR) in host cells, which may contribute to the pathogenesis of COVID-19. To understand the complex interplay between SARS-Co-V2 infection and UPR signaling, we examined the effects of acute pre-existing ER stress on SARS-Co-V2 infectivity. Methods: Huh-7 cells were treated with Tunicamycin (TUN) and Thapsigargin (THA) prior to SARS-CoV-2pp transduction (48 h p.i.) to induce ER stress. Pseudo-typed particles (SARS-CoV-2pp) entry into host cells was measured by Bright GloTM luciferase assay. Cell viability was assessed by cell titer Glo® luminescent assay. The mRNA and protein expression was evaluated by RT-qPCR and Western Blot. Results: TUN (5 µg/mL) and THA (1 µM) efficiently inhibited the entry of SARS-CoV-2pp into host cells without any cytotoxic effect. TUN and THA’s attenuation of virus entry was associated with differential modulation of ACE2 expression. Both TUN and THA significantly reduced the expression of stress-inducible ER chaperone GRP78/BiP in transduced cells. In contrast, the IRE1-XBP1s and PERK-eIF2α-ATF4-CHOP signaling pathways were downregulated with THA treatment, but not TUN in transduced cells. Insulin-mediated glucose uptake and phosphorylation of Ser307 IRS-1 and downstream p-AKT were enhanced with THA in transduced cells. Furthermore, TUN and THA differentially affected lipid metabolism and apoptotic signaling pathways. Conclusions: These findings suggest that short-term pre-existing ER stress prior to virus infection induces a specific UPR response in host cells capable of counteracting stress-inducible elements signaling, thereby depriving SARS-Co-V2 of essential components for entry and replication. Pharmacological manipulation of ER stress in host cells might provide new therapeutic strategies to alleviate SARS-CoV-2 infection.

Type 2 diabetes mellitus (T2DM) and cancer share common risk factors including obesity, inflammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate the PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and anti-apoptosis. The inhibition of the PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy; however, drug resistance poses a major problem in clinical settings resulting in limited efficacy of agents; thus, combination treatments with therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to develop and validate an instrument to measure Belonging in Surgery among surgical residents. Background: Belonging is the essential human need to maintain meaningful relationships and connections to one's community. Increased belongingness is associated with better well-being, job performance, and motivation to learn. However, no tools exist to measure belonging among surgical trainees. Methods: A panel of experts adapted a belonging instrument for use among United States surgery residents. After administration of the 28-item instrument to residents at a single institution, a Cronbach alpha was calculated to measure internal consistency, and exploratory principal component analyses were performed. Multiple iterations of analyses with successively smaller item samples suggested the instrument could be shortened. The expert panel was reconvened to shorten the instrument. Descriptive statistics measured demographic factors associated with Belonging in Surgery. Results: The overall response rate was 52% (114 responses). The Cronbach alpha among the 28 items was 0.94 (95% CI: 0.93-0.96). The exploratory principal component analyses and subsequent Promax rotation yielded 1 dominant component with an eigenvalue of 12.84 (70% of the variance). The expert panel narrowed the final instrument to 11 items with an overall Cronbach alpha of 0.90 (95% CI: 0.86, 0.92). Belonging in Surgery was significantly associated with race (Black and Asian residents scoring lower than White residents), graduating with one's original intern cohort (residents who graduated with their original class scoring higher than those that did not), and inversely correlated with resident stress level. Conclusions: An instrument to measure Belonging in Surgery was validated among surgical residents. With this instrument, Belonging in Surgery becomes a construct that may be used to investigate surgeon performance and well-being. [ABSTRACT FROM AUTHOR]

Actinomyces species has been described as a rare cause of primary breast, abdominal, and cutaneous infections, and can present as recurrent abscesses, tissue fibrosis, and fistulous draining sinuses, particularly in the setting of immune compromise. We present a case of a 48-year-old woman who underwent bilateral mastectomy with muscle sparing transverse rectus abdominus muscle free flap reconstruction thirteen years prior and developed recurrent abscesses in her reconstructed breast, ultimately attributable to chronic infection with Actinomyces. This is the first reported case of Actinomyces infection in the autologously reconstructed breast. Definitive treatment included surgical mastotomy and debridement with vacuum assisted wound closure and prolonged course of intravenous (IV) ampicillin-sulbactam followed by oral amoxicillin-clavulanate. Actinomyces infection of the breast may present as recurrent abscesses and requires a high index of suspicion to preserve the architecture of the autologously reconstructed breast.

Background: SARS-Co-V2 infection can induce ER stress-associated activation of unfolded protein response (UPR) in host cells, which may contribute to the pathogenesis of COVID-19. To understand the complex interplay between SARS-Co-V2 infection and UPR signaling, we examined the effects of acute pre-existing ER stress on SARS-Co-V2 infectivity. Methods: Huh-7 cells were treated with Tunicamycin (TUN) and Thapsigargin (THA) prior to SARS-CoV-2pp transduction (48 h p.i.) to induce ER stress. Pseudo-typed particles (SARS-CoV-2pp) entry into host cells was measured by Bright GloTM luciferase assay. Cell viability was assessed by cell titer Glo® luminescent assay. The mRNA and protein expression was evaluated by RT-qPCR and Western Blot. Results: TUN (5 µg/mL) and THA (1 µM) efficiently inhibited the entry of SARS-CoV-2pp into host cells without any cytotoxic effect. TUN and THA's attenuation of virus entry was associated with differential modulation of ACE2 expression. Both TUN and THA significantly reduced the expression of stress-inducible ER chaperone GRP78/BiP in transduced cells. In contrast, the IRE1-XBP1s and PERK-eIF2α-ATF4-CHOP signaling pathways were downregulated with THA treatment, but not TUN in transduced cells. Insulin-mediated glucose uptake and phosphorylation of Ser307 IRS-1 and downstream p-AKT were enhanced with THA in transduced cells. Furthermore, TUN and THA differentially affected lipid metabolism and apoptotic signaling pathways. Conclusions: These findings suggest that short-term pre-existing ER stress prior to virus infection induces a specific UPR response in host cells capable of counteracting stress-inducible elements signaling, thereby depriving SARS-Co-V2 of essential components for entry and replication. Pharmacological manipulation of ER stress in host cells might provide new therapeutic strategies to alleviate SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]