Cyclic Fasting-Mimicking Diet Plus Bortezomib and Rituximab Is an Effective Treatment for Chronic Lymphocytic Leukemia.

Cyclic fasting-mimicking diet (FMD) is an experimental nutritional intervention with potent antitumor activity in preclinical models of solid malignancies. FMD cycles are also safe and active metabolically and immunologically in cancer patients. Here, we reported on the outcome of FMD cycles in two patients with chronic lymphocytic leukemia (CLL) and investigated the effects of fasting and FMD cycles in preclinical CLL models. Fasting-mimicking conditions in murine CLL models had mild cytotoxic effects, which resulted in apoptosis activation mediated in part by lowered insulin and IGF1 concentrations. In CLL cells, fasting conditions promoted an increase in proteasome activity that served as a starvation escape pathway. Pharmacologic inhibition of this escape mechanism with the proteasome inhibitor bortezomib resulted in a strong enhancement of the proapoptotic effects of starvation conditions in vitro. In mouse CLL models, combining cyclic fasting/FMD with bortezomib and rituximab, an anti-CD20 antibody, delayed CLL progression and resulted in significant prolongation of mouse survival. Overall, the effect of proteasome inhibition in combination with FMD cycles in promoting CLL death supports the targeting of starvation escape pathways as an effective treatment strategy that should be tested in clinical trials. SIGNIFICANCE: Chronic lymphocytic leukemia cells resist fasting-mimicking diet by inducing proteasome activation to escape starvation, which can be targeted using proteasome inhibition by bortezomib treatment to impede leukemia progression and prolong survival.

Long-term effects of early postnatal stress on Sertoli cells.

Sertoli cells are somatic cells in testis essential for spermatogenesis, that support the development, maturation, and differentiation of germ cells. Sertoli cells are metabolically highly active and physiologically regulated by external signals, particularly factors in the blood stream. In disease conditions, circulating pathological signals may affect Sertoli cells and consequentially, alter germ cells and fertility. While the effects of stress on reproductive cells have been well studied, how Sertoli cells respond to stress remains poorly characterized. We used a mouse model of early postnatal stress to assess the effects of stress on Sertoli cells. We developed an improved strategy based on intracellular stainings and obtained enriched preparations of Sertoli cells from exposed males. We show that adult Sertoli cells have impaired electron transport chain (ETC) pathways and that several components of ETC complexes particularly complex I, III, and IV are persistently affected. We identify serum as potential mediator of the effects of stress on Sertoli cells by showing that it can recapitulate ETC alterations in primary cells. These results highlight Sertoli cells as cellular targets of stress in early life that can keep a trace of exposure until adulthood.

Factors Associated With Psychological Disturbances During the COVID-19 Pandemic: Multicountry Online Study.

BACKGROUND: Accumulating evidence suggests that the COVID-19 pandemic has negatively impacted the mental health of individuals. However, the susceptibility of individuals to be impacted by the pandemic is variable, suggesting potential influences of specific factors related to participants' demographics, attitudes, and practices. OBJECTIVE: We aimed to identify the factors associated with psychological symptoms related to the effects of the first wave of the pandemic in a multicountry cohort of internet users. METHODS: This study anonymously screened 13,332 internet users worldwide for acute psychological symptoms related to the COVID-19 pandemic from March 29 to April 14, 2020, during the first wave of the pandemic amidst strict lockdown conditions. A total of 12,817 responses were considered valid. Moreover, 1077 participants from Europe were screened a second time from May 15 to May 30, 2020, to ascertain the presence of psychological effects after the ease down of restrictions. RESULTS: Female gender, pre-existing psychiatric conditions, and prior exposure to trauma were identified as notable factors associated with increased psychological symptoms during the first wave of COVID-19 (P<.001). The same factors, in addition to being related to someone who died due to COVID-19 and using social media more than usual, were associated with persistence of psychological disturbances in the limited second assessment of European participants after the restrictions had relatively eased (P<.001). Optimism, ability to share concerns with family and friends like usual, positive prediction about COVID-19, and daily exercise were related to fewer psychological symptoms in both assessments (P<.001). CONCLUSIONS: This study highlights the significant impact of the COVID-19 pandemic at the worldwide level on the mental health of internet users and elucidates prominent associations with their demographics, history of psychiatric disease risk factors, household conditions, certain personality traits, and attitudes toward COVID-19.

Worsening of Preexisting Psychiatric Conditions During the COVID-19 Pandemic.

Objectives: To ascertain factors associated with worsening of psychiatric conditions during the coronavirus disease 2019 (COVID-19) pandemic. Methods: This study anonymously examined 2,734 psychiatric patients worldwide for worsening of their preexisting psychiatric conditions during the COVID-19 pandemic. An independent clinical investigation of 318 psychiatric patients from United States was used for verification. Results: Valid responses mainly from 12 featured countries indicated self-reported worsening of psychiatric conditions in two-thirds of the patients assessed that was through their significantly higher scores on scales for general psychological disturbance, posttraumatic stress disorder, and depression. Female gender, feeling no control of the situation, reporting dissatisfaction with the response of the state during the COVID-19 pandemic, and reduced interaction with family and friends increased the worsening of preexisting psychiatric conditions, whereas optimism, ability to share concerns with family and friends, and using social media like usual were associated with less worsening. An independent clinical investigation from the United States confirmed worsening of psychiatric conditions during the COVID-19 pandemic based on identification of new symptoms that necessitated clinical interventions such as dose adjustment or starting new medications in more than half of the patients. Conclusions: More than half of the patients are experiencing worsening of their psychiatric conditions during the COVID-19 pandemic.