Angioimmunoblastic T cell lymphoma (AITL) and peripheral T cell lymphoma not-otherwise-specified (PTCL, NOS) have poor prognosis and lack actionable targets for directed therapies in most cases. Here we report the identification of FYN-TRAF3IP2 as a novel highly recurrent oncogenic gene fusion in AITL and PTCL, NOS tumors. Mechanistically, FYN-TRAF3IP2 triggers aberrant NF-κB activity by engaging TRAF6 downstream of T cell receptor signaling. Moreover, FYN-TRAF3IP2 expression in hematopoietic progenitors induces NF-κB-driven T cell transformation in mice and cooperates with loss of the Tet2 tumor suppressor in PTCL development. Therapeutically, abrogation of NF-κB signaling in FYN-TRAF3IP2-induced tumors via IκB kinase inhibitors delivers strong anti-lymphoma effects in vitro and in vivo. These results formally demonstrate an oncogenic role for FYN-TRAF3IP2 and NF-κB signaling in the pathogenesis of PTCL.

Prostate cancer is the third most common cancer in men globally, and the most common cancer among men in the United States. Dietary choices may play an important role in developing prostate cancer; in particular, a higher dairy product intake has been associated with an increased risk of developing prostate cancer. The overall positive association between milk consumption and the risk of prostate cancer development and prostate cancer mortality has been well documented in multiple epidemiological studies. However, there is limited literature on the association between types of milk, as classified by fat content (skim, low fat, and whole), and the risk of developing prostate cancer. When further examining current state of the literature on this topic, there is a number of epidemiologic studies assessing the relationship between prostate cancer and milk consumption. On the contrary, very few experimental studies explore this topic. Further experimental research may be necessary to examine the relationship between dairy and dairy products consumption and the increased risk of development of prostate cancer. At this time, there are no formal clinical recommendations regarding dairy products consumption for patients who are at risk of prostate cancer development or who have a history of prostate cancer. In this manuscript, we sought to systematically review the existing literature on the association between milk consumption classified by fat content, and the risk of developing prostate cancer. These findings may be useful for the clinicians who provide recommendations for the patients at risk of developing prostate cancer.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Post-natal mammary gland development is a complex process in which epithelial proliferation and branching of lactiferous ducts is followed by extensive formation of lobuloalveolar units that produce milk. Classical nuclear factor-kappa B (NF-κB) p65/p50 transcription factors are dynamically induced in the mammary gland during pregnancy, and inhibitor of NF-κB-alpha (IκB-α) deficiency leads to hyperplasia of the mammary epithelium. To further elucidate the role of NF-κB factors in mammary development, we examined NF-κB subunit expression in the mammary glands of transgenic mice expressing the IκB-α S32/36A super-repressor (SR) protein under control of the mouse mammary tumor virus (MMTV)-long terminal repeat promoter, in which mammary gland development is transiently delayed, but not completely blocked. Developmental recovery correlated with induction of RelB/p52 NF-κB complexes, which failed to interact with an IκB-α fusion protein and potently induced cyclin D1 and c-myc promoter activities. Activation of IκB-α kinase alpha (IKKα) and NF-κB inducing kinase (NIK) was detected by day 5.5, and were hypothesized to be responsible for the induction of ReIB/p52. In support of this hypothesis, we found that constitutively active IKKα induced p52, RelB, and cyclin D1 in untransformed mammary epithelial cells. Moreover, mammary tumors induced by high-dose 7,12-dimethylbenz(a)anthracene (DMBA) treatment in wild type FVB/N mice, displayed increased RelB/p52 binding activity. These results implicate activation of RelB/p52 complexes by the alternative NF-κB signaling pathway in branching of lateral ducts and alveolar development during mammary gland development, and in mammary carcinogenesis. / 2031-01-01

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13466号 / 論医博第2253号 / 新制||医||1055(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村川 泰裕, 教授 中島 貴子, 教授 藤田 恭之 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Amyloidosis involves extracellular deposition of abnormal proteins/fibrils with potential end organ damage. AL type amyloidosis is one subtype and a clonal plasma cell disorder. A 74-year-old completely asymptomatic male presented with progressive renal dysfunction. Work up with serum protein electrophoresis (SPEP) and immunofixation revealed monoclonal IgG Lamda spike of 1.1 g/dL. Urine protein electrophoresis noted Bence Jones proteins. Notable labs, hemoglobin 10.6 g/dL, calcium was 8.2 mg/dL, and creatinine 2.4 mg/dL. Quantitative immunoglobulins IgA, IgG, and IgM, were 59 mg/dL, 1,939 mg/dL, and 23 mg/dL, respectively. Lambda and Kappa free light chains 26.37 mg/L and 127.87 mg/L, respectively, with a ratio of 0.21. Skeletal survey noted a 4 mm lucency of the left frontal bone. Bone marrow biopsy confirmed 21% plasma cells. Renal biopsy revealed AL lambda light chain confirming final diagnosis AL Lambda light chain Amyloidosis and IgG Lambda Multiple Myeloma. Treatment with daratumumab, cyclophosphamide, bortezomib, and dexamethasone initiated. His clinical course was complicated by COVID 19 infection prior to treatment initiation and with congestive heart failure secondary to cardiac amyloidosis (elevated Troponin and Brain Natriuretic Peptide level) during induction therapy requiring hospitalization, diuresis and optimization of cardiac medications. Very Good Partial Response (VGPR) noted after 2 cycles and near Complete Response (CR) after 4 cycles. Patient was evaluated and approved for Stem cell transplant (SCT) but decided against SCT and has now proceeded to single agent daratumumab maintenance. Amyloidosis is an uncommon disease seen in older adults (median age 64) with deposition of fibrils composed of low molecular weight subunits derived from normal proteins. Various subtypes and protien/fibrils include AL amyloidosis (immunoglobulin light chain), hereditary/ familial transthyretin amyloidosis (mutated transthyretin, apolipoprotien, fibrinogen A, lysozyme), wildtype transthyretin Amyoidosis/senile amyloidosis (unmutated transthyretin) and AA amyloidosis (serum amyloid A fibril). AL amyloidosis is a systemic disorder that presents with nephrotic syndrome or restrictive cardiomyopathy (as in this case). Other presentations involve peripheral neuropathy, hepatomegaly, macroglossia, arthropathy with “shoulder pad” sign, bleeding diathesis, purpura including “racoon eyes”. Biopsy of the affected organ (kidney, liver, fat pad aspirate, bone marrow) with Congo red staining confirms the histologic diagnosis. Amyloid light chains can be confirmed with proteomic analysis (mass spectrometry or immuno-electron-microscopy). AL amyloidosis treatment entails high dose chemotherapy and autologous SCT. Long term prognosis in advanced stage is poor. Survival can be short (4-6 months), heart failure causing about 50% of deaths. Daratumumab-regimens offer a 40-55% CR and with SCT data (83% five year and 50% ten-year survival) the outlook is improving.

Breast cancer is the most commonly diagnosed cancer in women with an estimated 287,850 cases in 2022. Approximately 684,000 deaths each year are associated with breast cancer across the world. Risk factors of breast cancer include increased estrogen exposure, family history of breast cancer, and environmental factors. Treatment of breast cancer is highly dependent on the presence of HER2, estrogen, and progesterone receptors. Breast cancers that present with increased receptors for estrogen, progesterone, and HER2 are typically the least aggressive and the easiest to treat. The percentage of cases in the United States associated with hormone receptor positive and HER-2 negative or positive are approximately 82%. Absence of receptors for estrogen, progesterone, and HER2 is known as triple negative breast cancer. In the United States, only about 10% of cases are associated with this form. However, it is considered the most aggressive and difficult to treat. Two emerging flavonoids known as CT1 and CT3 have shown cytotoxic activity against cell lines that represent some of the most common breast cancers: MCF7, MDA-MB-231, and SKBr3. CT1 and CT3 were extracted from the leaves of Chromolaena tacotana using a Soxhlet extractor and the compounds then underwent isolation and purification. The cells were then treated with CT1 or CT3 at concentrations of 5, 10, 20, 40 and 80 µM. MTT assays were then used to determine cell viability. MDA-MB-231, the most aggressive type of breast cancer cells, responded to both CT1 and CT3. The most profound cytotoxic effects of CT1 were seen with MCF7 and MDA-MB-231, while CT3 exhibited a greater toxicity against SKBr3 cells. Preliminary results indicate that CT1 and CT3 target the MEK-ERK signaling pathway. Further studies need to be completed to determine mechanistically how these compounds lead to receptor-independent toxicity.

Introduction: Oxidative stress is a disruption in the balance of free radicals and antioxidants. Cancer patients have very high levels of oxidative stress due to radiation and chemotherapy. This imbalance from the oxidative stress can stimulate cancerous growth, as well abnormal cellular growth. Oxidative stress is due, in part, to lipid per-oxidation from cancer treatments, generating electrophilic aldehydes that attack abnormal, as well as healthy cells. A way to combat the amount of oxidative stress to protect healthy cells is to increase antioxidant defenses through the diet. Antioxidants are chemicals that help stop free radical formation and prevent cell damage. Traditional high antioxidant foods include fruits, vegetables, low saturated- fats, and high fiber foods. During cancer treatments the patient generally has a decreased sense of appetite, as nausea and emesis are common side effects. A “treat” food, like a Reese’s peanut butter cup might be able to stimulate a cancer patient’s appetite, and thus meeting some of their much-needed dietary nutrients. By transforming this popular dessert treat into something that could aid with oxidative stress may be beneficial to this population. The objective of this study was to create an appetizing and nutritionally functional Reese’s peanut butter cup alternative with enhanced antioxidants. Methods: A common Reese’s cup recipe was taken and adapted for more nutrient rich ingredients. The milk chocolate of the original control recipe for Reese's cup was substituted in the variant dessert cup with dark chocolate cacao nibs. The peanut butter was replaced by tahini, and the sugar was replaced by dates in the control and variant, respectively. Proximate analyses for the nutritional content of both dessert cups was collected. Analyses included: Total cal/g using bomb calorimetry, antioxidant potential by a ferric reducing ability of plasma (FRAP), Soxhlet for lipid determination, kjeldahl for protein determination, and fiber via a ANKOM Fiber Analyzer. Results: Calories for the control yielded 5961 cal/g, and the variant, 6007.5 cal/g. The absorbance data for FRAP was 2.9996 and 4.5426, for the control and variant respectively. Lipid content was 46.65% for the control (% Ether Extract (Crude Fat)) and 46.9% for the variant (% Ether Extract (Crude Fat)). Protein content for the control was 6.25%, and 9.65% for the variant. Analysis for dietary fiber found insoluble dietary fiber to be 26.6% and soluble dietary fiber 0% for the control. The variant’s insoluble dietary fiber content was 21.4% and soluble dietary fiber 8.7%. Finally, dry matter was 98.6% for the control, and 97.4% for the variant. Conclusion: Data collected showed the greatest differences between antioxidants, fiber, and protein, with the variant having the highest percent content of each nutrient. This research has shown that a dessert alternative can support patients undergoing cancer therapies through the provision of necessary calories and antioxidants. Future research is needed to compare the specific fatty acid content of these two products

Dehydropyrrolizidine alkaloids (DHPAs) are a large group of globally important plant-derived pro-toxins that can contaminate or are naturally present in animal feed and the human food supply as well as herbal supplements. Their bioactive metabolites are potentially hepatotoxic, pneumotoxic, genotoxic and carcinogenic. Due to the difficulty in obtaining sufficient quantities of purified DHPAs, toxicity studies have largely relied on single intraperitoneal injections in rodent models, and carcinogenicity studies have been limited to a small handful of the hundreds of isolated DHPAs. To assess the relative toxicity of structurally diverse DHPAs in a more biologically relevant manner, male California White chicks were dosed orally with 0.01, 0.04, 0.13, or 0.26 mmol of seven different DHPAs and three DHPA N-oxides kg-1 bodyweight for 7 days. DHPAs were grouped in relation to their toxicity based on clinical, serum biochemical, and histopathological evaluations as well as tissue adduct accumulation rates. Using the same model, a reduced extract from comfrey, a commonly used DHPA containing herb, was compared to its two major constituent DHPAs, intermedine and lycopsamine. Based on the same parameters, the comfrey extract was more toxic than pure lycopsamine or intermedine. Addressing the need for a more sensitive carcinogenicity model, male heterozygous p53 knockout mice were treated with riddelliine 5, 15 or 45 mg kg–1 bodyweight day-1 by oral gavage for 14 days, or given a long-term treatment of riddelliine 1 mg kg-1 bodyweight day–1 in pelleted feed for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose-responsive manner (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). The most common neoplasm was hepatic hemangiosarcoma, which is consistent with previously published lifetime rodent studies. The results of this research demonstrate that the California White chick model is sensitive for comparison of DHPA toxicity, and data obtained from this research can be used to validate previous DHPA toxicity research. It also demonstrates that comfrey toxicity may have been previously underestimated. The heterozygous p53 knockout mouse model is beneficial for further investigation of comparative carcinogenesis of structurally and toxicologically different DHPAs and their N-oxides.

Pancoast tumors are a distinct entity seen mostly in non-small cell carcinoma of the lung. We present a case of a Pancoast tumor in newly diagnosed squamous cell carcinoma of the lung. A 56-year old female with a 40-pack year smoking history, presented with several weeks duration of right shoulder pain, radiating down her arm. Symptoms were aggravated with movement and slightly improved with rest and non-steroidal analgesics She had no other known medical history. Physical therapy provided little relief. Subsequently, magnetic resonance imaging (MRI) of the cervical spine from an outside facility revealed a large right apical lung mass, involving the T2 thoracic spine and sternum. She denied chest pain, shortness of breath, weight loss, or edema of the face or neck. Range of motion of right upper extremity was limited due to pain. Ptosis and miosis of the right eye were detected. Days after the MRI, the patient presented to the hospital for intractable right upper extremity pain. Comprehensive imaging including positron emission tomography scan and MRI of the brain were done. The right apical lung mass was suggestive of a Pancoast tumor, measuring 5.3 x 5.5 x 6.9 cm in size, extending into the medial portion of the upper mediastinum. The tumor abutted the apical pleura and partially encased the right subclavian artery. There was destruction of the first and second ribs and portions of the right T1 and T2 vertebral bodies along with right hilar and lower paratracheal adenopathy. Biopsy of the mass confirmed moderately differentiated, invasive squamous cell carcinoma of the lung, assessed to be Stage IIIB and unresectable. Pain control was achieved, and the patient was discharged. Treatment was initiated with concurrent radiation and chemotherapy with cisplatin and etoposide. Pancoast tumors, also known as superior sulcus tumors, were first noted in 1838 but not well defined at the time. In 1924 and 1932, American radiologist, Henry Pancoast, further described them as carcinomas of unknown origin of the chest apex. They occur in 3-5% of lung cancers, most commonly in non-small cell carcinoma. By definition, a Pancoast tumor must invade parietal pleura and cause pain, paresthesia, or neurologic dysfunction. Less than 50% of these tumors are resectable. They may involve the lower cervical and/or upper thoracic spines, first and second ribs, brachial plexus, and subclavian vessels. Involvement of paravertebral sympathetic chains can lead to Horner syndrome with a prevalence up to 40%. Neurologic compromise may cause upper extremity weakness, muscular atrophy, and paresthesia. In 5% of cases, they can cause spinal cord compression and paraplegia. Five-year survival is reported to be less than 10% if there is vertebral body invasion. In locally advanced lung cancers including Pancoast tumors, treatment can include neoadjuvant chemoradiation with subsequent resection. However due to the extensiveness and complexity of this patient’s tumors, resection was not amenable. Evaluation for Pancoast tumor may be warranted in those with lung cancer risk with acute musculoskeletal/neurologic complaints. Treatment is initiated promptly, based on stage and histology.

The experiments presented were designed to test the hypothesis that the well-known carcinogen, benzo[a]pyrene has epigenetic effects, specifically the ability to alter cytosine methylation patterns. MCF-7 and MDA-MB-231 human breast cancer cells were treated for a period of sixty days with 100 nM benzo[a]pyrene. The methylation status of two genes, Ecadherin and GSTP 1 were examined using methyl-specific PCR and Southern blot analysis. After sixty days, no detectable change in methylation was observed. Evidence exists that de novo methylation is a consequence of transcriptional inactivity. Benzo[a]pyrene can contribute to transcriptional repression by sequestering the transcription factor, Spl. To test this hypothesis in our system, MCF-7 cells were transiently transfected with a reporter construct containing Sp 1 sites. These experiments demonstrated an 8.4 fold increase in reporter gene activity over a promoterless control plasmid; however, a difference could not be established between benzo[a]pyrene-treated and untreated cells.